Novel quinuclidine derivatives and medicinal compositions containing the same

ABSTRACT

A compound of formula (I), wherein B is a phenyl ring, a 5 to 10 membered heteroaromatic group containing one or more heteroatoms, or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, or biphenyl group; R 1 , R 2  and R 3  each independently represent a hydrogen or halogen atom, or a hydroxy group, a phenyl group, —OR 7 , —SR 7 , —NR 7 R 8 , —NHCOR 7 , —CONR 7 R 8 , —CN, —NO 2 , —COOR 7  or CF 3  group, or a strait or branched, substituted or unsubstituted lower alkyl group, wherein R 7  and R 8  each independently represent a hydrogen atom, a straight or branched lower alkyl group, or together form an alicyclic ring; or R 1  and R 2  together form an aromatic or alicyclic ring or a heterocyclic group. n is an integer from 0 to 4; A represents a group selected from —CH 2 —, —CH═CR 9 —, —CR 9 ═CH—, —CR 9 R 10 —, —CO—, —O—, —S—, —S(O)—, —S(O) 2 — and NR 9 , wherein R 9  and R 10  each independently represent a hydrogen atom, a straight or branched lower alkyl group, or together form an alicyclic ring; m is an integer from 0 to 8, provided that when m=0, A is not —CH 2 —; p is an integer from 1 to 2 and the substitution in the azonia bicyclic ring may be in the 2, 3 or 4 position including all possible configurations of the asymmetric carbons; R 4  represents a group of structure: (Formulae II) wherein R 11  represents a hydrogen or halogen atom, a hydroxy group, an alkoxy group, a nitro group, a cyano group, —CO 2 R 12  or —NR 12 R 13 , wherein R 12  and R 13  are identical or different and are selected from hydrogen and straight or branched lower alkyl groups, or a straight or branched, substituted or unsubstituted lower alkyl group; R 5  represents an alkyl group of 1 to 7 carbon atoms, an alkenyl group containing 2 to 7 carbon atoms, or a group of formula (III) wherein q=1 or 2 and R 11  iss a defined above; R 6  represents a hydrogen atom, a hydroxy group, a methyl group or a —CH 2 OH group; and X −  represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

[0001] This invention relates to new therapeutically useful quinuclidinederivatives, to some processes for their preparation and topharmaceutical compositions containing them.

[0002] The novel structures according to the invention areantimuscarinic agents with a potent and long lasting effect. Inparticular, these compounds show high affinity for muscarinic M3receptors. This subtype of muscarinic receptor is present in glands andsmooth muscle and mediates the excitatory effects of the parasympatheticsystem on glandular secretion and on the contraction of visceral smoothmuscle (Chapter 6, Cholinergic Transmission, in H. P. Rang et al.,Pharmacology, Churchill Livingstone, New York, 1995).

[0003] M3 antagonists are therefore known to be useful for treatingdiseases characterised by an increased parasympathetic tone, byexcessive glandular secretion or by smooth muscle contraction (R. M.Eglen and S. S. Hegde, (1997), Drug News Perspect., 10(8):462-469).

[0004] Examples of this kind of diseases are respiratory disorders suchas chronic obstructive pulmonary disease (COPD), bronchitis, bronchialhyperreactivity, asthma, cough and rhinitis; urological disorders suchas urinary incontinence, pollakiuria, neurogenic or unstable bladder,cystospasm and chronic cystitis; gastrointestinal disorders such asirritable bowel syndrome, spastic colitis, diverticulitis and pepticulceration; and cardiovascular disorders such as vagally induced sinusbradycardia (Chapter 7, Muscaeinic Receptor Agonists and Antagonists, inGoodman and Gilman's The Pharmacological Basis of Therapeutics, 10theedition, McGraw Hill, Ney York, 2001).

[0005] The compounds of the invention can be used alone or inassociation with other drugs commonly regarded as effective in thetreatment of these diseases. For example, they can be administered incombination with β₂-agonists, steroids, antiallergic drugs,phosphodiesterase IV inhibitors an/or leukotriene D4 (LTD4) antagonistsfor simultaneous, separate or sequential use in the treatment of arespiratory disease. The claimed compounds are useful for the treatmentof the respiratory diseases detailed above in association withβ₂-agonists, steroids, antiallergic drugs or phosphodiesterase IVinhibitors.

[0006] Compounds with related structures have been described asanti-cholinergic and/or anti-spasmodics agents in several patents.

[0007] For example, FR 2012964 describes quinuclidinol derivatives ofthe formula

[0008] in which R is H, OH or an alkyl group having 1 to 4 carbon atoms;R¹ is a phenyl or thienyl group; and R² is a cyclohexyl, cyclopentyl orthienyl group, or, when R is H, R¹ and R² together with the carbon atomto which they are attached, form a tricyclic group of the formula:

[0009] in which X is —O—, —S— or —CH₂—,

[0010] or an acid addition or quaternary ammonium salt thereof.

[0011] In United States patent U.S. Pat. No. 4,465,834 a class ofanticholinergic drugs having the formula

[0012] are described, in which R¹ is a carbocyclic or branched aliphaticgroup of 3 to 8 carbon atoms (such as phenyl, cyclohexyl, cyclopentyl,cyclopropyl, cycloheptyl, and isopropyl), R² is a branched or linearaliphatic group containing 3 to 10 carbon atoms with 1 or 2 olefinic oracetylenic bonds, or is a phenylethinyl, a styryl, or an ethynyl group,and R³ Is an alkyl or cyclic group of 4 to 12 carbon atoms containig atertiary amino nitrogen. The compounds of the invention are also claimedas either the free base or the acid-addition and quaternary ammoniumsalt forms thereof.

[0013] In U.S. Pat. No. 4,843,074 products of formula

[0014] are described, wherein X=H, halogen, lower alkyl, lower alkoxy,hydroxy and R=morpholinyl, thiomorpholinyl, piperidinyl,1,4-dioxa-8-azaspiro[4,5]decanyl, 4-(2,6-dimetylmorpholinyl),4-ketopiperidinyl, 4-hydroxypiperidinyl, 4-substituted piperazinyl. Thelower alkyl halide quaternary salts and pharmaceutically acceptable acidaddition salts are included in the invention.

[0015] U.S. Pat. No. 4,644,003 describes esters of 3-quinuclidinol ofalpha disubstituted glicolic acids

[0016] and their pharmaceutically acceptable salts,

[0017] where R is phenyl, unsubstituted or substituted up to threesubstituents including alkoxy, halogen, nitro, amino, alkylamino,dialkylamino, acylamino, and trifluoromethyl; and wherein R¹ ishydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,alkyloxyalkyl, cycloalkyloxyalkyl, haloalkyl or haloalkenyl.

[0018] In WO 92/04346 are described compounds of formula

[0019] and their pharmaceutically acceptable salts, where X is a phenyl(optionally substituted) or a thienyl group and “Het” is either (a) afive membered nitrogen-containing heterocyclic group, (b) an oxadiazolylor thiadiazolyl group, or (c) a six membered nitrogen-containingheterocyclic group, and m is 1 or 2. (For a more detailed description,see the above mentioned publication)

[0020] Azoniabicyclic compounds of a general structure related to thecompounds of the invention are disclosed in WO 01/04118.

[0021] The present invention provides new quinuclidine ester derivativeswith potent antagonist activity at muscarinic M3 receptors which havethe chemical structure described in formula (I):

[0022] wherein B is a phenyl ring, a 5 to 10-membered heteroaromaticgroup containing one or more heteroatoms, or a naphthalenyl,5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, or biphenyl group;R¹, R² and R³ each independently represent a hydrogen or halogen atom,or a hydroxy group, a phenyl group, —OR⁷, —SR⁷, —NR⁷R⁸, —NHCOR⁷,—CONR⁷R⁸, —CN, —NO₂, —COOR⁷ or —CF₃ group, or a straight or branched,substituted or unsubstituted lower alkyl group, wherein R⁷ and R⁸ eachindependently represent a hydrogen atom, a straight or branched loweralkyl group, or together form an alicyclic ring; or R¹ and R² togetherform an aromatic or alicyclic ring or a heterocyclic group;

[0023] n is an integer from 0 to 4;

[0024] A represents a group selected from —CH₂—, —CH═CR⁹—, —CR⁹═CH—,—CR⁹R¹⁰—, —CO—, —O—, —S—, —S(O)—, —S(O)₂— and —NR⁹—, wherein R⁹ and R¹⁰each independently represent a hydrogen atom, a straight or branchedlower alkyl group, or together form an alicyclic ring;

[0025] m is an integer from 0 to 8, provided that when m=0, A is not—CH₂—;

[0026] p is an integer from 1 to 2 and the substitution in the azoniabicyclic ring may be in the 2, 3 or 4 position including all possibleconfigurations of the asymmetric carbons;

[0027] R⁴ represents a group of structure:

[0028] wherein R¹¹ represents a hydrogen or halogen atom, a hydroxygroup, an alkoxy group, a nitro group, a cyano group, —CO₂R¹² or—N^(R12R13) wherein R¹² and R¹³ are identical or different and areselected from hydrogen and straight or branched lower alkyl groups, or astraight or branched, substituted or unsubstituted lower alkyl group;

[0029] R⁵ represents an alkyl group of 1 to 7 carbon atoms, an alkenylgroup containing 2 to 7 carbon atoms, an alkynyl group containing 2 to 7carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms, or a group offormula

[0030] wherein q=1 or 2 and R¹¹ is as defined above;

[0031] R⁶ represents a hydrogen atom, a hydroxy group, a methyl group ora —CH₂OH group. The asymmetric carbon in the alpha position to the estergroup, which is substituted by R⁴, R⁵, and R⁶ may have R or Sconfiguration.

[0032] X⁻ represents a pharmaceutically acceptable anion of a mono orpolyvalent acid.

[0033] In the quaternary ammonium compounds of the present inventionrepresented by formula (I), an equivalent of an anion (X⁻) is associatedwith the positive charge of the N atom. X⁻ may be an anion of variousmineral acids such as, for example, chloride, bromide, iodide, sulfate,nitrate, phosphate, or an anion of an organic acid such as, for example,acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate,malate, mandelate, trifluoroacetate, methanesulfonate andp-toluenesulfonate. X⁻ is preferably an anion selected from chloride,bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinateor trifluoroacetate. More preferably X⁻ is chloride, bromide,trifluoroacetate or methanesulphonate.

[0034] The compounds of the present invention represented by the formula(I) described above, which may have one or more asymmetric carbons,include all the possible stereoisomers. The single isomers and mixturesof the isomers fall within the scope of the present invention.

[0035] As used herein, an alkyl group is typically a lower alkyl group.A lower alkyl group preferably contains 1 to 8, preferably 1 to 6 andmore preferably 1 to 4 carbon atoms. In particular it is preferred thatsuch an alkyl group is represented by a methyl, ethyl, propyl, includingi-propyl, or butyl including a n-butyl, sec-butyl and tert-butyl group.An alkyl group containing 1 to 7 carbon atoms as mentioned herein, suchas that represented by R⁵, may be a C₁₋₄ alkyl group as mentioned aboveor a straight or branched pentyl, hexyl or heptyl group.

[0036] Optionally substituted lower alkyl groups mentioned hereininclude straight or branched alkyl groups containing from 1 to 6,preferably from 1 to 4, carbon atoms as mentioned above, which may beunsubstituted or substituted in any position by one or moresubstituents, for example by 1, 2 or 3 substituents. When two or moresubstituents are present, each substituent may be the same or different.The substituent(s) are typically halogen atoms or hydroxy or alkoxygroups, preferably hydroxy or alkoxy groups.

[0037] Alkenyl groups having 2 to 7 carbon atoms mentioned herein, suchas those represented by the group R⁵, are straight or branched groupssuch as ethenyl, or straight or branched propenyl, butenyl, pentenyl,hexenyl or heptenyl. The double bond may be in any position in thealkenyl group, such as on the terminal bond.

[0038] Alkynyl groups having 2 to 7 carbon atoms mentioned herein, suchas those represented by the group. R⁵, are straight or branched groupssuch as ethynyl, propynyl or straight or branched butynyl, pentynyl,hexynyl or heptynyl. The triple bond may be in any position in thealkynyl group, such as on the terminal bond.

[0039] Alkoxy groups mentioned herein, such as those that may be presentin the group B, are typically lower alkoxy groups, that is groupscontaining from 1 to 6 carbon atoms, preferably from 1 to 4 carbonatoms, the hydrocarbon chain being branched or straight. Preferredalkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,sec-butoxy and t-butoxy.

[0040] Cycloalkyl groups and alicyclic groups mentioned herein, unlessotherwise specified, typically contain from 3 to 8 carbon atoms,preferably from 3 to 6 carbon atoms. Cycloalkyl groups and alicydlicrings of 3 to 6 carbon atoms include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. Cycloalkyl groups containing from 3 to 7carbon atoms include cycloalkyl groups of 3 to 6 carbon atoms andcycloheptyl.

[0041] The aromatic ring mentioned in relation to R¹ and R² typicallycontains from 5 to 14, preferably 5 to 10 carbon atoms. Examples ofaromatic groups include cyclopentadienyl, phenyl and naphthalenyl.

[0042] A heterocyclic or heteroaromatic group mentioned herein istypically a 5 to 10 membered group, such as a 5, 6 or 7 membered group,containing one or more heteroatoms selected from N, S and O. Typically,1, 2, 3 or 4 heteroatoms are present, preferably 1 or 2 heteroatoms. Aheterocyclic or heteroaromatic group may be a single ring or two or morefused rings wherein at least one ring contains a heteroatom. Examples ofheterocyclic groups include piperidyl, pyrrolidyl, piperazinyl,morpholinyl, thiomorpholinyl, pyrrolyl, imidazolyl, imidazolidinyl,pyrazolinyl, indolinyl, isoindolinyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl,quinolizinyl, isoquinolyl, qutnolyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, quinuclidinyl,triazolyl, pyrazolyl, tetrazolyl and thienyl. Examples of heteroaromaticgroups include pyridyl, thienyl, furyl, pyrrolyl, imidazolyl,benzothiazolyl, pyridinyl, pyrazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl,phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,triazolyl and pyrazolyl.

[0043] As used herein a halogen atom includes a fluorine, chlorine,bromine or iodine atom, typically a fluorine, chlorine or bromine atom.

[0044] Preferred compounds of formula (I) are those wherein B representsa phenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl,5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, imidazolyl orbenzothiazolyl group, in particular a phenyl, pyrrolyl, thienyl, furyl,biphenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl orbenzo[1,3]dioxolyl group such as a phenyl, thienyl or pyrrolyl group.

[0045] B may be unsubstituted or substituted with one, two or threegroups (R¹ to R³) which may be in any position on the ring. Typically itis unsubstituted or substituted with one group, for example when B is aphenyl group it may be substituted in the 2, 3 or 4 position. Typically,R¹, R² and R³ each independently represent a hydrogen or halogen atom,or a hydroxy, methyl, tert-butyl, —CH₂OH, 3-hydroxypropyl, —OMe, —NMe₂,—NHCOMe, —CONH₂, —CN, —NO₂, —COOMe or —CF₃ group, in particular ahydrogen, fluorine or chlorine atom or a hydroxy, methyl, —CH₂OH, —OMe,—NMe₂, —NHCOMe, —CONH₂, —CN, —NO₂, —COOMe or —CF₃ group. The mostpreferred groups R¹, R² and R³ are hydrogen, fluorine, chlorine orhydroxy.

[0046] Examples of substituted phenyl groups which may represent B aretolyl including o-, m- and p-tolyl, 3-cyanophenyl, 2-, 3- and4-hydroxyphenyl and 2-, 3- and 4-fluorophenyl.

[0047] Preferred compounds of formula (I) are those wherein n=0 or 1; mis an integer from 1 to 6, particularly 1, 2 or 3; and A represents a—CH₂—, —CH═CH—, —CO—, —NMe—, —O— or —S— group, in particular a —CH₂—,—CH═CH—, —O— or —S— group, for example a —CH₂—, —CH═CH— or —O— group.

[0048] More preferred salts of formula (I) are those wherein theazoniabicyclo group is substituted on the nitrogen atom with a3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl,4-phenylbutyl, 3-phenylpropyl, 3-(2-hydroxyphenoxy)propyl,3-(4-fluorophenoxy)propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl,2-thien-2-ylethyl, 3-thien-2-ylpropyl, 3-phenylaminopropyl,3-(methylphenylamino)propyl, 3-phenylsulfanylpropyl, 3-o-tolyloxypropyl,3-(2,4,6-trimethylphenoxy)propyl,3-(2-tert-butyl-6-methylphenoxy)propyl, 3-(biphenyl-4-yloxy)propyl,3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-propyl,3-(naphthalen-2-yloxy)propyl, 3-(naphthalen-1-yloxy)propyl,3-(2-chlorophenoxy)propyl, 3-(2,4-difluorophenoxy)propyl,3-(3-trifluoromethylphenoxy)propyl, 3-(3-cyanophenoxy)propyl,3-(4-cyanophenoxy)propyl, 3-(3-methoxyphenoxy)propyl,3-(4-methoxyphenoxy)propyl, 3-(benzo[1,3]dioxol-5-yloxy)propyl,3-(2-carbamoylphenoxy)propyl, 3-(3-dimethylaminophenoxy)propyl,3-(4-nitrophenoxy)propyl, 3-(3-nitrophenoxy)propyl,3-(4-acetylaminophenoxy)propyl, 3-(4-methoxycarbonylphenoxy)propyl,3-[4-(3-hydroxypropyl)phenoxy]propyl, 3-(2-hydroxymethylphenoxy)propyl,3-(3-hydroxymethylphenoxy)propyl, 3-(4-hydroxymethylphenoxy)propyl,3-(2-hydroxyphenoxy)propyl, 3-(4-hydroxyphenoxy)propyl,3-(3-hydroxyphenoxy)propyl, 4-oxo-4-thien-2-ylbutyl,3-(1−methyl-[1H]-imidazol-2-ylsulfanyl)propyl,3-(benzothiazol-2-yloxy)propyl, 3-benzyloxypropyl,6-(4-phenylbutoxy)hexyl, 4-phenoxybutyl, 4-(4-fluorophenyl)-4-oxobutylor 4-oxo-4-phenylbutyl group. Especially preferred salts are thosewherein the azoniabicyclo group is substituted on the nitrogen atom witha 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl,3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl,3-thien-2-ylpropyl group, 4-oxo-4-thien-2-ylbutyl, 2-benzyloxyethyl,3-o-tolyloxypropyl, 3-(3-cyanophenoxy)propyl,3-(methylphenylamino)propyl, 3-phenylsulfanylpropyl, 4-oxophenylbutyl,3-(2-chlorophenoxy)propyl, 3-(2,4-difluorophenoxy)propyl,3-(4-methoxyphenoxy)propyl, 3-(benzo[1,3]dioxol-5-yloxy)propyl. Examplesof especially preferred salts are those wherein the azoniabicyclo groupis substituted on the nitrogen atom with a 3-phenoxypropyl,2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl,3-(3-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl or3-thien-2-ylpropyl group.

[0049] Further preferred compounds of formula (I) are those wherein R⁴represents a phenyl, 2-thienyl, 3-thienyl, 2-furyl or 3-furyl group. R¹¹preferably represents a hydrogen or halogen atom or an unsubstitutedlower alkyl group such as methyl or ethyl. Most preferably R¹¹ is ahydrogen atom. Therefore, for example, R⁴ may represent an unsubstitutedphenyl, 2-thienyl or 2-furyl group. Alternatively, R⁴ may represent anunsubstituted phenyl or 2-thienyl group. Preferably, R⁵ represents abenzyl, phenethyl, cyclopentyl, cyclohexyl, C₂₋₅ alkyl, C₂₋₅ alkenyl orC₂₋₅alkynyl group, particularly a cyclopentyl, cyclohexyl, pentyl,allyl, vinyl, propynyl, phenethyl or benzyl group. Alternatively, R⁵represents a benzyl, cyclopentyl, cyclohexyl, C₂₋₅ alkyl, C₂₋₅ alkenylor C₂₋₅ alkynyl group, particularly a cyclopentyl, cyclohexyl, pentyl,allyl, vinyl, propynyl or benzyl group. The asymmetric carbon alpha tothe ester group, which is substituted by R⁴, R⁵ and R⁶ may have R or Sconfiguration.

[0050] Preferred compounds of formula (I) are those wherein the group—O—CO—C(R⁴)(RW)(R⁶) represents a group selected from2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy; 2,3-diphenylpropionyloxy;2-hydroxymethyl-2,3-diphenylpropionyloxy;2-hydroxy-2,3-diphenylpropionyloxy;2-hydroxy-3-phenyl-2-thien-2-ylpropionyloxy;2-hydroxy-2-thien-2-ylpent-4-enoyloxy;2-hydroxy-2-thien-2-ylheptanoyloxy;2-hydroxy-2-thien-2-ylpent-3-ynoyloxy;2-hydroxy-2-thien-2-ylbut-3-enoyloxy;2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy;2-cyclohexyl-2-hydroxy-2-phenylacetoxy;2-cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy,2-cyclopentyl-2-hydroxy-2-phenylacetoxy,2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy and2-hydroxy-4-phenyl-2-thien-2-ylbutanoyloxy. Examples of the group—O—CO—C(R⁴)(R⁵)(R⁶) are 2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy;2,3-diphenylpropionyloxy; 2-hydroxymethyl-2,3-diphenylpropionyloxy;2-hydroxy-2,3-diphenylpropionyloxy;2-hydroxy-3-phenyl-2-thien-2-ylpropionyloxy;2-hydroxy-2-thien-2-ylpent-4-enoyloxy;2-hydroxy-2-thien-2-ylheptanoyloxy;2-hydroxy-2-thien-2-ylpent-3-ynoyloxy;2-hydroxy-2-thien-2-ylbut-3-enoyloxy;2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy;2-cyclohexyl-2-hydroxy-2-phenylacetoxy and2-cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy.

[0051] In the most preferred embodiments of the invention p is 2, theazoniabicyclo[2.2.2]octane ring is substituted in the 3 position, andthis subsituted carbon atom has (R)-configuration.

[0052] The following compounds are intended to illustrate but not tolimit the scope of the present invention:

[0053](3R)-3-(2,3-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0054](3R)-3-(2,3-Diphenylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0055](3R)-3-[(2*)-2-Hydroxymethyl-2,3-diphenylpropionyloxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (diastereomer 1)

[0056](3R)-3-[(2*)-2-Hydroxymethyl-2,3-diphenylpropionyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (diastereomer 1)

[0057](3R)-3-[(2′)-2-Hydroxymethyl-2,3-diphenylpropionyloxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (diastereomer 2)

[0058](3R)-3-[(2)-2-Hydroxymethyl-2,3-diphenylproplonyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (diastereomer 2)

[0059](3R)-3-[(2′)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide (diastereomer 1)

[0060](3R)-3-[(2)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide (diastereomer 1)

[0061](3R)-3-[(2′)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (diastereomer 2)

[0062](3R)-3-[(2*)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (diastereomer 2)

[0063](3R)-3-(2-Hydroxy-3-phenyl-2-thien-2-ylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0064](3R)-3-(2-Hydroxy-3-phenyl-2-thien-2-ylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0065](3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide

[0066](3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0067](3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide

[0068](3R)-3-(2-Hydroxy-2-thien-2-ylheptanoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0069](3R)-3-(2-Hydroxy-2-thien-2-ylheptanoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0070](3R)-3-(2-Hydroxy-2-thien-2-ylpent-3-ynoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0071](3R)-3-(2-Hydroxy-2-thien-2-ylpent-3-ynoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0072](3R)-3-(2-Hydroxy-2-thien-2-ylbut-3-enoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0073](3R)-3-(2-Hydroxy-2-thien-2-ylbut-3-enoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0074](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide

[0075](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0076](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide

[0077](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0078](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0079](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0080](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0081](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(4-oxo-4-thien-2-ylbutyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0082](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[4-(4-fluorophenyl)-4-oxobutyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0083](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0084]1-(2-Benzyloxyethyl)-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0085](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-o-tolyloxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0086]1-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0087](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(naphthalen-1-yloxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0088](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(methylphenylamino)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0089](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0090](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0091](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(2,4,6-trimethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0092]1-[3-(2-Chlorophenoxy)propyl-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0093](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(3-trifluoromethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0094]1-[3-(Biphenyl-4-yloxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0095](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(2,4-difluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0096](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0097](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0098]1-[3-(Benzo[1,3]dioxol-5-yloxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0099]1-[3-(2-Carbamoylphenoxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0100](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(3-dimethylaminophenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0101]1-[3-(4-Acetylaminophenoxy)propyl-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicycld[2.2.2]octanetrifluoroacetate

[0102](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-methoxycarbonylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0103](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-nitrophenoxy)propyl]-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0104](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0105](3R)-3-[(2R)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide

[0106](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0107](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0108](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0109](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0110](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0111](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0112](3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0113](3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0114](3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0115](3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0116](3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0117](3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0118](3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0119](3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0120](3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0121](3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0122](3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0123](3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0124](3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0125](3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0126](3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0127](3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0128](3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0129](3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0130](3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0131](3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0132](3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0133](3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0134](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0135](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0136](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0137](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0138](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0139](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0140](3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0141](3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0142]1-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2S)-2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0143](3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0144](3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0145]1-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2R)-2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0146](3R)-3-(2-Hydroxy-4-phenyl-2-thien-2-ylbutanoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0147](3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide

[0148](3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0149](3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0150]4-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0151]4[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

[0152] ((*): Configuration not assigned; either the (2R)- or the(2S)-isomers of the above compounds may be produced).

[0153] The present invention also provides processes for preparingcompounds of formula (I). The quaternary ammonium derivatives of generalformula (I), may be prepared by reaction of an alkylating agent ofgeneral formula (II) with compounds of general formula (III). Informulae (I), (II) and (Ill), R¹, R², R³, B, A, X⁻, R⁴, R⁵, R⁶, n, m andp are as defined above.

[0154] In formula (II), W represents any suitable leaving group, such asa group X as defined above. Preferably, W represents a group X.

[0155] This alkylation reaction may be carried out by two differentexperimental procedures, a) and b) which are described above. Inparticular method b) provides a new experimental process, using solidphase extraction methodologies, that allows the parallel preparation ofseveral compounds. Methods a) and b) are described in the experimentalsection. If W represents a group other than X, the quaternary ammoniumsalt of formula (I) is produced from the product of method (a) or (b) bycarrying out an exchange reaction according to standard methods toreplace the anion W⁻ with the desired anion X⁻.

[0156] Compounds of general formula (II) which are not commerciallyavailable have been prepared by synthesis according to standard methods.For example, compounds wherein n=0 and A=—O—, —S— or —NR⁹—, wherein R⁹is as defined above, were obtained by reaction of the correspondingaromatic derivative or its potassium salt with an alkylating agent ofgeneral formula Y—(CH₂)m-X, wherein X may be a halogen and Y may be ahalogen or a sulphonate ester. In other examples, compounds of generalformula (II), where n≧1 were synthesised from the corresponding alcoholderivative of general formula (IV) by known methods

[0157] wherein R¹, R², R³, n, m, and A are as defined above.

[0158] Compounds of general formula (III) may be prepared by differentmethods. These procedures are illustrated in the following schemes anddetailed in the experimental section.

[0159] Method c)

[0160] Compounds of general formula (III) may be synthesised bytransesterification of a compound of formula (V) with a compound offormula (VI).

[0161] in which formulae R⁴, R⁵, R⁶ and p are as defined above and Lrepresents a leaving group. For example L may be a chlorine atom, animidazol-1-yl group, or a group —OR¹⁴ wherein R¹⁴ represents a straightor branched, substituted or unsubstituted lower alkyl group or a —COR¹⁵group wherein R¹⁵ represents —COCR⁴R⁵R⁶. Typically L is —OR¹⁴ whereinR¹⁴ is methyl, ethyl or propyl, or L is an imidazol-1-yl group.

[0162] Intermediates of formula (VI) may be prepared by standard methodsdescribed in the literature, for example as in FR 2012964.

[0163] Method d)

[0164] Compounds of formula (III) where R⁶ is a hydroxy group and p, R⁴and R⁵ are as described above, may also be prepared from the glyoxalateesters of general formula (VII) by reaction with the correspondingGrignard reagent.

[0165] Compounds of general formula (VII) may be prepared by standardmethods described in the literature (WO 01/04118; WO 92/04346)

[0166] Method e)

[0167] Compounds of formula (III) where R⁶ is a group —CH₂OH, and p, R⁴and R⁵ are as described above, may also be prepared from thecorresponding compound of formula (III), where R⁶ is an hydrogen atom,by reaction with formaldehyde in basic conditions. (Organic SynthesesCollective Volumes, VII, 271-274, (1990); WO 93/06098)

[0168] As will be described in the experimental part, the diastereomersof the compounds of formula (III) may be separated by conventionalmethods, for example by column chromatography or crystallisation.

[0169] The following compounds are compounds of general formula (III)which have not been described before: compounds of formula (III)

[0170] wherein p, R4, R5 and R6 are as defined above, the substituent onthe azabicyclo group is at position 3 or 4 and when it is at position 3this substituted carbon has an enantiomerically pure R or Sconfiguration, provided that when R4 is a 3-thienyl group and R5 is acyclohexyl group R6 is not a hydroxy group.

[0171] The substituent on the azabicyclo group is preferably at position3 and may have R or S configuration. The carbon substituted by R⁴, R⁵and R⁶ may have R or S configuration. The compound may be a singleisomer.

[0172] Examples of the new compounds of formula (III) include:

[0173] (2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=+19.7° (c=1, CHCl₃)).

[0174] (2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=−14.2° (c=1, CHCl₃)).

[0175] (2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=+21.1° (c=1, CHCl₃)).

[0176] (2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=−23.5° (c=1, CHCl₃)).

[0177] (2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid1-azabicyclo[2.2.2]oct-4-yl ester ([α]²² _(D)=−27.6° (c=1, CHCl₃)).

[0178] In particular:

[0179] (2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicydlo[2.2.2]oct-3-yl ester ([α]²² _(D)=+19.7° (c=1, CHCl₃)).

[0180] (2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=−14.2° (c=1, CHCl₃)).

[0181] (2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=+21.1° (c=1, CHCl₃)).

[0182] (2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=−23.5° (c=1, CHCl₃)).

[0183] Compounds of formula (V) could be:

[0184] 4-hydroxy-1-azabicyclo[2.2.1]heptane, described in WO93/15080

[0185] 4-hydroxy-1-azabicyclo[2.2.2]octane, described in Grob, C. A.et.al. Helv. Chim. Acta (1958), 41, 1184-1190

[0186] (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane or(3S)-3-hydroxy-1-azabicyclo[2.2.2]octane, described in Ringdahl, R. ActaPharm Suec. (1979), 16, 281-283 and commercially available from CUChemie Uetikon GmbH.

[0187] The following examples are intended to illustrate, but not tolimit, the experimental procedures that have been described above.

[0188] The structures of the prepared compounds were confirmed by ¹H-NMRand MS. The NMR spectra were recorded using a Varian 300 MHz instrumentand chemical shifts are expressed as parts per million (δ) from theinternal reference tetramethylsilane. Their purity was determined byHPLC, using reverse phase chromatography on a Waters instrument, withvalues greater than 95% being obtained. Molecular ions were obtained byelectrospray ionization mass spectrometry on a Hewlett Packardinstrument. Optical rotations were obtained using a PERKIN-ELMER 241 MCPolarimeter.

[0189] Method -a—

EXAMPLE 13

[0190] Preparation of(3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneBromide

[0191] 250 mg (0.81 mmol) of 2-Hydroxy-2-thien-2-ylpent-4-enoic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester, Intermediate I-3, were dissolvedIn 5 ml of acetonitrile and 7.5 ml of chloroform. To this solution wereadded 0.63 ml (4.1 mmol) of phenoxypropylbromide. After stirring for 48h at room temperature under a N₂ atmosphere, solvents were evaporated.Ether was added and the mixture stirred. The solid obtained was filteredand washed several times with ether. The yield was 0.3 g (71%) of thetitle compound as a mixture of diastereomers; mp: 157° C.

[0192]¹H-NMR (DMSO-d₆): δ 1.70-2.05 (m, 4H), 2.05-2.35 (m, 3H),2.70-2.83 (m, 1H), 2.90-3.02 (m, 1H), 3.25-3.60 (m, 7H), 3.82-3.97 (m,1H); 3.974.10 (m, 2H), 5.05-5.25 (m, 3H), 5.70-5.90 (m, 1H), 6.50 (d,1H, OH), 6.90-7.05 (m, 4H), 7.10-7.20 (m, 1H), 7.27-7.35 (m, 2H), 7.45(m, 1H).

[0193] MS: [M-Br]⁺: 442.

[0194] Method -b—

EXAMPLE 35

[0195] Preparation of(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(naphthalen-1-yloxy)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0196] 20 mg (0.06 mmols) of(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester (Intermediate I-15a), weredissolved in 1 ml of DMSO. To this solution 66 mg (0.30 mmol) of3-(naphthalen-1-yloxy)propyl chloride were added. After stirringovernight at room temperature, the mixture was purified by solid phaseextraction with a cation exchange Mega Bond Elut cartridge, previouslyconditioned at pH=7.5 with 0.1 M NaH₂PO4 buffer. The reaction mixturewas applied to the cartridge and washed first with 2 ml of DMSO and thenthree times with 5 ml of CH₃CN, rinsing away all starting materials. Theammonium derivative was eluted with 5 ml of 0.03 M TFA solution inCH₃CN:CHCl₃ (2:1). This solution was neutralized with 300 mg ofpoly(4-vinylpyridine), filtered and evaporated to dryness. The yield was10 mg (26%) of title compound.

[0197]¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.80-2.10 (m, 4H),2.20-2.37 (m, 3H), 2.75-2.92 (m, 1H), 3.20-3.65 (m, 7H), 3.90-4.05 (m,1H), 4.15-4.30 (m, 2H), 5.15-5.22 (m, 1H), 6.24 (s, 1H, OH), 6.95-7.05(m, 2H), 7.15-7.20 (m, 1H), 7.40-7.60 (m, 5H), 7.85-7.95 (m, 1H),8.20-8.25 (m, 1H).

[0198] MS: [M-CF₃COO]⁺: 520

[0199] The spatial configurations of the compounds of general formula(III) have been deduced from the configurations of their correspondingacids. These were determined either comparing the values of [a]obtainedwith the values described in the literature or applying the CircularDichroism (CD) technique.

[0200] Since the CD curve of (2S)-2-Cyclohexyl-2-hydroxy-2-phenylaceticacid is known (A. Tambuté and A. Collet, Bulletin de la Société Chimiquede France, 1984, No 1-2, pages II77 to II82) and all the acids evaluatedare structurally very similar to(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid, it can be assumed thatthe relative positions of the aryl, cycloalkyl, carboxyl and hydroxylsubstituents may be identified by comparison of their respective Δεvalues. The resulting configurations have been expressed as R or Saccording to Cahn-Ingol-Prelog system. (see TABLE 1)

[0201] The curves of CD spectra were recorded with a Jasco-720spectrophotometer (Software J-700) from 0.43 mM MeOH solutions of thesamples in 1 mm cells at 25° C. TABLE I Circular Dichroism Compound[α]²² _(D) λ (nm) Δε (M⁻¹cm⁻¹) Configuration(+)-2-Cyclohexyl-2-hydroxy-2- +23.1° 224 +12.1  S^(a) phenylacetic acid  (c = 1.4, EtOH) (−)-2-Cyclohexyl-2-hydroxy-2- −23.60° 224 −11.7 Rphenylacetic acid   (c = 1.4, EtOH) (−)-2-Cyclopentyl-2-hydroxy-2-−1.52° 224 −8.93  R^(b) phenylacetic acid (c = 3, MeOH)(+)-2-Cyclopentyl-2-hydroxy-2- +6.63° 233 +4.18 R thien-2-ylaceticacid^(c,1) (c = 1, EtOH) (−)-2-Cyclopentyl-2-hydroxy-2- −6.44° 233 −4.19S thien-2-ylacetic acid^(c,2) (c = 1, EtOH)(−)-2-Cyclohexyl-2-hydroxy-2- −15.1° 235 −5.40 S thien-2-ylaceticacid^(c,3) (c = 1, EtOH) (+)-2-Cyclopentyl-2-fur-2-yl-2- +31.95° 230+7.64 S hydroxyacetic acid (c = 1, EtOH) (−)-2-Cyclopentyl-2-fur-2-yl-2-−32.10° 230 −7.44 R hydroxyacetic acid (c = 1, EtOH)(+)-2-Cyclohexyl-2-fur-2-yl-2- +40.9° 230 +10.9 S hydroxyacetic acid (c= 1, EtOH) (−)-2-Cyclohexyl-2-fur-2-yl-2- −39.7° 230 −10.8 Rhydroxyacetic acid (c = 1, EtOH)

[0202] Method -c—

[0203] Methyl ester derivatives of general formula (VI) were prepared bystandard methods described in the literature or following the proceduresdescribed in the examples: Intermediates I-9, I-10, I-11, I-12, I-13.

[0204] Intermediate I-1

[0205] Preparation of 2-Hydroxy-2-thien-2-ylheptanoic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester

[0206] 2.7 g of 2-Hydroxy-2-thien-2-ylheptanoic acid methyl ester(Intermediate I-9) (0.011 mol) were dissolved in 70 ml of toluene. Tothis solution were added 1.63 g (0.0128 mol) of(3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 0.18 g (0.0045 mol) of HNa(60% dispersion in mineral oil). The mixture was refluxed withcontinuous removal of distillate with replacement with fresh toluenewhen necessary for 1 hour. The cooled mixture was extracted with 1N HClacid, the aqueous layer washed with ether, basified with K₂CO₃ andextracted with CHCl₃. The organic layer was washed with water, driedover MgSO₄ and evaporated. The yield was 2.85 g (76%) of the titleproduct as a mixture of diastereomers, structure confirmed by ¹H-NMR.

[0207]¹H-NMR (CDCl₃): δ 0.80-0.95 (m, 3H), 1.20-1.40 (m, 6H), 1.40-1.90(m, 4H), 1.95-2.25 (m, 3H), 2.50-2.95 (m, 5H), 3.10-3.30 (m, 1H), 4.4(bs, 1H, OH), 4.82-4.94 (m, 1H), 6.94-7.02 (m, 1H), 7.06-7.14 (m, 1H),7.20-7.26 (m, 1H).

[0208] MS: [M+1]⁺: 338.

[0209] (Compound also prepared following method d)

[0210] Intermediate I-2

[0211] Preparation of 2,3-Diphenylpropionic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester

[0212] Prepared using the same method as for Intermediate I-1, but from2,3-diphenylpropionic acid methyl ester. The yield was 1.71 g (61.5%) ofthe title product as a mixture of diastereomers.

[0213]¹H-NMR (DMSO): δ 1.05-1.20 (m, 1H), 1.30-1.60 (m, 3H), 1.65-1.75(m, 1H), 2.10-2.20 (m, 1H), 2.30-2.70 (m, 4H), 2.85-3.10 (m, 2H),3.20-3.40 (m, 1H), 3.95-4.10 (m, 1H), 4.50-4.65 (m, 1H), 7.10-7.45 (m,10H).

[0214] MS: [M+1]⁺: 336

[0215] (2,3-diphenylpropionic acid methyl ester may be prepared from the2,3-diphenylproplonic acid, commercially available)

[0216] Intermediate I-3

[0217] Preparation of 2-Hydroxy-2-thien-2-ylpent-4-enoic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0218] Prepared using the same method as for Intermediate I-1, but from2-Hydroxy-2-thien-2-ylpent-4-enoic acid methyl ester (IntermediateI-10). The yield was 1.76 g (63.1%) of the title product as a mixture ofdiastereomers.

[0219]¹H-NMR (CDCl₃): δ 1.25-1.80 (m, 4H), 1.80-2.10 (m, 1H), 2.50-3.05(m, 7H), 3.10-3.35 (m, 2H), 4.55 (bs, 1H, OH), 4.75-4.95 (m, 1H),5.10-5.30 (m, 2H), 5.70-5.95 (m, 1H), 6.95-7.05 (m, 1H), 7.10-7.20 (m,1H), 7.20-7.30 (m, 1H).

[0220] MS: [M+1]⁺: 308

[0221] (Compound also prepared following method d)

[0222] Intermediate I-4

[0223] Preparation of 2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0224] Prepared using the same method as for Intermediate I-1, but from13.73 g (0.057 mol) of 2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acidmethyl ester (Intermediate I-11) dissolved in 350 ml of toluene, 8.6 g(0.067 mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 1.37 g(0.0342 mol) of HNa (60% dispersion in mineral oil). The oil obtained(10.33 g) was purified by chromatography on silica gel eluting withchloroform/methanol/ammonia 97:3:0.3. Appropiate fractions were combinedand evaporated to obtain the two diastereomers: I-4a and I-4b.

[0225] Intermediate I-4a

[0226] (2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester

[0227] 1.59 g of an oil corresponding to the first eluted diastereomerwas triturated with a mixture of ethyl ether/isopropyl ether 1:1, togive 0.82 g (8.6%, based on single isomer) of a solid whose structurewas confirmed by ¹H-NMR as a pure diastereomer.

[0228] [α]²² _(D)=+21.1° (c=1, CHCl₃)).

[0229]¹H-NMR (CDCl₃): δ 1.10-1.45 (m, 8H), 1.45-1.60 (m, 2H), 1.60-1.85(m, 4H), 1.94-2.02 (m, 1H), 2.26-2.38 (m, 1H), 2.70-2.92 (m, 5H),3.20-3.28 (m, 1H), 3.78 (bs, 1H, OH), 4.90 (m, 1H), 6.30-6.40 (m, 2H),7.40 (m, 1H).

[0230] MS: [M+1]⁺: 334.

[0231] Intermediate I-4a was hydrolised (EtOH/NaOH 2N, 2 h r.t, 1 h 60°C.), to yield (+)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid: [α]²²_(D)=+40.9° (c=1, EtOH). Configuration S was assigned (See TABLE 1)

[0232] Intermediate I-4b

[0233] (2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester

[0234] 1.12 g of an oil corresponding to the second eluted diastereomerwas triturated with a mixture of ethyl ether/isopropyl ether 1:1, togive 0.57 g (6%, based on single isomer) of a solid whose structure wasconfirmed by ¹H-NMR as a pure diastereomer. [α]²² _(D)=−23.5° (c=1,CHCl₃)).

[0235]¹H-NMR (CDCl₃): δ 1.10-1.50 (m, 8H), 1.50-1.90 (m, 6H), 2.04-2.12(m, 1H), 2.24-2.36 (m, 1H), 2.46-2.58 (m, 1H), 2.68-2.94 (m, 4H),3.12-3.22 (m, 1H), 3.77 (bs, 1H, OH), 4.90 (m, 1H), 6.40 (m, 2H), 7.42(m, 1H)

[0236] MS: [M+1]⁺: 334.

[0237] Intermediate I-4b was hydrolised (EtOH/NaOH 2N, 2 h r.t, 1 h 60°C.), to yield (−)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid: [α]²²_(D)=−39.7° (c=1, EtOH).

[0238] Configuration R was assigned. (See TABLE 1)

[0239] Intermediate I-5

[0240] Preparation of 2-Cyclopentyl-2-hydroxy-2-phenylacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester

[0241] Prepared using the same method as for Intermediate I-1, but from13.5 g (0.0576 mol) of 2-Cyclopentyl-2-hydroxy-2-phenylacetic acidmethyl ester (commercially available) dissolved in 350 ml of toluene,8.0 g (0.063 mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 0.91 g(0.023 mol) of HNa (60% dispersion in mineral oil). The yield was 13.1 g(69%) of the title product as an oil mixture of diastereomers, structureconfirmed by ¹H-NMR. The two diastereomers I-5a and I-5b were separatedafter several crystallizations.

[0242] Intermediate I-5a

[0243] (2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0244] Several treatments of the oil mixture of diastereomers withdiferent mixtures of diethyl ether/hexane and diisopropyl ether/hexane(cooling at −60° C.) yield 4.3 g of a white solid identified by ¹H-RMNas an enriched diastereomer I-5a. This solid was recrystallised twicefrom diethyl ether/hexane (cooling at 0° C.) to yield 2 g (21%) of purediastereomer.

[0245] [α]²² _(D)=−10.8° (c=1, CHCl₃)

[0246]¹H-NMR (CDCl₃): δ 1.25-1.80 (m, 11H), 1.80-1.95 (m, 1H), 2.05-2.15(m, 1H), 2.40-2.50 (m, 1H), 2.62-3.05 (m, 5H), 3.05-3.18 (m, 1H), 3.80(s, 1H, OH), 4.85-4.90 (m, 1H), 7.22-7.42 (m, 3H), 7.60-7.75 (m, 2H).

[0247] Intermediate I-5a was hydrolised (EtOH/NaOH 2N, 2 h r.t. and 2 hat 60° C.) to give (−)-2-Cyclopentyl-2-hydroxy-2-phenylacetic acid as apure enantiomer: [α]²² _(D)=−1.52° (c=3, MeOH). This value was assignedto the R configuration provided that in the literature (M. Mitsuya etal.; Bioorg. Med. Chem., (1999), 7, 2555-2567) the R enantiomer has beendescribed with [α]²² _(D)=−1.9° (c=3, MeOH). (See TABLE 1)

[0248] Intermediate I-5b

[0249] (2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0250] The mother liquors from the first solid I-5a were evaporated andtreated with maleic acid in isopropanol/diethyl ether. After cooling at0-5° C., 7.0 g of a white solid were obtained and identified by ¹H-RMNas the maleate salt of a mixture enriched with the second diastereomerI-5b. After three crystallisations of this product fromacetonitrileldiethyl ether (1:2.2), 2.4 g (18.7%, based on free base) ofthe maleate salt enriched with the second diastereomer I-5b (in aproportion 88:12 as determined by H-RMN) were obtained.

[0251] This maleate salt enriched with the second diastereomer I-5b(88:12) was treated with CHCl₃ and K₂CO₃ solution to obtain the freebase.

[0252] I-5b (Free Base):

[0253] [α]²² _(D)=+19.5° (c=1, CHCl₃)

[0254]¹H-NMR (CDCl₃): δ 1.20-1.80 (m, 12H), 1.85-2.0 (m, 1H), 2.60-3.05(m, 6H), 3.20-3.35 (m, 1H), 3.80 (s, 1H, OH), 4.75-4.82 (m; 1H),7.20-7.45 (m, 3H), 7.55-7.75 (m, 2H). The signals corresponding to thediastereomer I-5a (12%) were observed at 2.05-2.15, 2.40-2.50,3.05-3.18, 4.85-4.90 ppm.

[0255] Configuration S was assigned in view of the results obtained forIntermediate I-5a. (See TABLE 1).

[0256] Intermediate I-6

[0257] Preparation of 2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0258] Prepared using the same method as for Intermediate I-1, but from16.2 g (0.064 mol) of 2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic acidmethyl ester (Intermediate I-12), dissolved in 400 ml of toluene, 9.5 g(0.074 mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 1.51 g(0.038 mol) of HNa (60% dispersion In mineral oil). The oil obtained(10.97 g) was purified by chromatography on silica gel, eluting withchloroform/methanol/ammonia 95:5:0.5, to obtain 8.97 g of a pure productas a mixture of diastereomers, structure confirmed by ¹H-RMN. Threecrystallisations of this mixture from ethyl ether yield 1.68 g (15.2%)of a pure diastereomer (Intermediate I-6a). The mother liquors of thecrystallisations were enriched with the other diastereomer (IntermediateI-6b).

[0259] Intermediate I-6a

[0260] (2S)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0261] [α]²² _(D)=−16.5° (c=1, CHCl₃).

[0262]¹H-NMR (CDCl₃): δ 1.05-1.85 (m, 13H), 1.85-2.0 (m, 1H), 2.0-2.16(m, 2H), 2.58-2.68 (m, 1H), 2.70-3.0 (m, 4H), 3.14-3.24 (m, 1H), 4.0 (s,1H, OH), 4.90-5.0 (m, 1H), 6.95-7.05 (m, 1H), 7.10-7.15 (m, 1H),7.20-7.30 (m, 1H).

[0263] MS: [M+1]⁺: 350.

[0264] Intermediate I-6a was hydrolised (EtOH/NaOH 2N, 2 h r.t, 1 h 60°C.), to yield (−)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic acid: [α]²²_(D)=−15.1° (c=1, EtOH).

[0265] Configuration S was assigned. (See TABLE 1).

[0266] Intermediate I-6b

[0267] (2R)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3(R)-yl Ester.

[0268]¹H-NMR (CDCl₃): δ 1.05-2.0 (m, 14H), 2.0-2.20 (m, 2H), 2.65-3.02(m, 5H), 3.24-3.36 (m, 1H), 4.0 (s, 1H, OH), 4.804.90 (m, 1H), 6.95-7.05(m, 1H), 7.10-7.20 (m, 1H), 7.20-7.30 (m, 1H).

[0269] The signals corresponding to the Intermediate I-6a (aprox. 25%)were observed at 2.58-2.68, 3.14-3.24 and 4.90-5.0 ppm.

[0270] MS: [M+1]⁺: 350.

[0271] Configuration R was assigned in view of the results obtained withIntermediate I-6a. (See TABLE 1).

[0272] Intermediate I-7

[0273] (2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic Acid(3S)-1-azabicyclo[2.2.2]oct-3-yl ester.

[0274] 510 mg (0.00225 mol) of(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid (obtained byhydrolysis of Intermediate I-15a) were dissolved in 7 ml of DMF. Thissolution was stirred at room temperature and 638 mg (0.00393 mol) of1,1′-carbonyldiimidazol were added in several portions. After 4.5 h thereaction mixture was cooled to 0° C. and 315 mg (0.00248 mol) of(3S)-3-hydroxy-1-azabicyclo[2.2.2]octane and 83 mg (0.0021 mol) of HNa(60% dispersion in mineral oil) were added thereto. After stirring 112 hat room temperature the reaction mixture was treated with water andextracted three times with diethyl ether. The organic layers werecombined, washed with brine and dried over anhydrous magnesium sulfate.The solvent was evaporated and the residue was purified by silica gelcolumn chromatography (eluent CHCl₆/MeOH 15:1) to obtain 360 mg (47.6%)of the title product as an oil, structure confirmed by ¹H-RMN.

[0275] [α]²² _(D)=−18.16° (c=1, CHCl₃)

[0276]¹H-NMR (CDCl₃): δ (Same description as in Intermediate I-15b)

[0277] MS: [M+1]⁺: 336.

[0278] Intermediate I-8

[0279] (2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetic Acid1-azabicyclo[2.2.2]oct-4-yl Ester.

[0280] Prepared using the same method as for Intermediate I-7, but froma solution of 660 mg (0.00282 mol) of(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid (obtained by hydrolysisof Intermediate I-16a) in 9 ml of DMF, 548 mg (0.00338 mol) of1,1′-carbonyldiimidazol, 394 mg (0.0031 mol) of4-hydroxy-1-azabicyclo[2.2.2]octane and 104 mg (0.00259 mol) of HNa (60%dispersion in mineral oil). After 44 h of stirring at room temperaturethe reaction mixture was treated with water and extracted three timeswith diethyl ether. The organic layers were combined, washed with brineand dried over anhydrous magnesium sulfate. The solvent was evaporatedand the residue was purified by silica gel column chromatography elutingwith CHCl₃ to CHCl₃/MeOH 15:1. The yield was 300 mg (31%) of the titleproduct.

[0281] [α]²² _(D)=−27.6° (c=1, CHCl₃)

[0282]¹H-NMR (CDCl₃): δ 1.0-1.55 (m, 7H), 1.55-1.75 (m, 2H), 1.75-1.85(m, 1H), 1.85-2.05 (m, 6H), 2.10-2.22 (m, 1H), 2.90-3.10 (m, 6H),3.60-3.80 (bs, 1H, OH), 7.20-7.40 (m, 3H), 7.57-7.67 (m, 2H).

[0283] MS: [M+1]⁺: 344.

[0284] Intermediate I-9

[0285] Preparation of 2-Hydroxy-2-thien-2-ylheptanoic Acid Methyl Ester.

[0286] 50 ml of a ether solution of 0.0338 mol of pentylmagnesiumbromide prepared from 5.1 g of 1-bromopentane (0.0338 mol) and 0.0372mols of magnesium, were added to a solution of 5 g of2-oxo-2-thien-2-ylacetic acid methyl ester dissolved in 40 ml of asolution of ether/THF (50:50), at −70° C. under a N₂ atmosphere. Themixture was stirred at this temperature for 10 minutes, and then warmedto room temperature. After 16 h, the reaction mixture was treated with asaturated solution of ammonium chloride and extracted three times withethyl acetate. The organic phases were combined, washed with water, anddried over MgSO₄. After removal of the solvent, the oil obtained waspurified by column chromatography (silica gel) using mixtures ofhexane/AcOEt (25:1 to 15:1) as eluent. The yield was 2.7 g (38%) of apure product, whose structure was confirmed by ¹H-NMR.

[0287]¹H-NMR (CDCl₃): δ 0.80-1.0 (m, 3H), 1.10-1.45 (m, 6H), 1.90-2.30(m, 2H), 3.80 (s, 3H), 4.05 (s, 1H, OH), 7.0 (m, 1H), 7.10 (m, 1H), 7.30(m, 1H).

[0288] (2-Oxo-2-thien-2-ylacetic acid methyl ester was prepared from thecommercially available 2-oxo-2-thien-2-ylacetic acid by a standardmethod).

[0289] Intermediate I-10

[0290] Preparation of 2-Hydroxy-2-thien-2-ylpent-4-enoic Acid MethylEster

[0291] Prepared using the same method as for Intermediate I-9. The yieldwas 1.92 g. 45.3%.

[0292]¹H-NMR (CDCl₃): δ 2.75-3.0 (m, 2H), 3.80 (s, 3H), 4.0 (s, 1H, OH),5.10-5.30 (m, 2H), 5.70-5.90 (m, 1H), 6.95-7.05 (m, 1H), 7.10-7.20 (m,1H), 7.25-7.35 (m, 1H).

[0293] MS: [M]⁺=212.

[0294] Intermediate I-11

[0295] Preparation of 2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic AcidMethyl Ester.

[0296] Prepared using the same method as for Intermediate I-9, but from73 ml (0.146 mol) of a solution of cyclohexylmagnesium chloride 2M indiethyl ether and 22.51 g (0.146 mol) of 2-fur-2-yl-2-oxoacetic acidmethyl ester (dissolved in 330 ml of THF). The oil obtained was purifiedby column chromatography (silica gel) using a mixture of hexane/AcOEt9:1 as eluent. After removal of the solvent 13.73 g (39%) of a pureproduct were obtained whose structure was confirmed by MS and ¹H-NMR.

[0297]¹H-NMR (CDCl₃): δ 1.05-1.75 (m, 6H), 1.75-1.95 (m, 4H), 2.20-2.40(m, 1H), 3.80 (s, 3H), 3.95 (s, 1H, OH), 6.30-6.50 (m, 2H), 7.35-7.45(m, 1H).

[0298] MS: [M]⁺: 238.

[0299] (2-Fur-2-yl-2-oxoacetic acid methyl ester was prepared from thecommercially available 2-fur-2-yl-2-oxoacetic acid by a standardmethod).

[0300] Intermediate I-12

[0301] Preparation of 2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic AcidMethyl Ester.

[0302] 98.6 ml (0.197 mol) of a 2M solution of Cyclohexylmagnesiumchloride in diethyl ether, were added to a solution of 27.97 g (0.164mol) of 2-oxo-2-thien-2-ylacetic acid methyl ester dissolved in 370 mlof THF, at −78° C. under a N₂ atmosphere. The mixture was stirred atthis temperature for 10 minutes, and then warmed to room temperature.After 1 h, the reaction mixture was treated with a saturated solution ofammonium chloride and extracted three times with ethyl acetate. Theorganic phases were combined, washed with water, and dried over MgSO₄.After removal of the solvent, the oil obtained was purified by columnchromatography (silica gel) using hexane/AcOEt 90:10 as eluent. Theyield was 16.2 g (39.5%) of a pure product, whose structure wasconfirmed by ¹H-NMR.

[0303]¹H-NMR (CDCl₃): δ 1.0-1.55 (m, 6H), 1.55-1.90 (m, 4H), 2.0-2.20(m, 1H), 3.80 (s, 3H), 4.0 (s, 1H, OH), 7.0 (m, 1H), 7.10 (m, 1H),7.20-7.30 (m, 1H).

[0304] MS: [M⁺]: 254.

[0305] (Intermediate I-12 is described in E. Atkinson et al. J. Med.Chem., (1977), Vol 20, No 12, 1612-1617)

[0306] Intermediate I-13

[0307] Preparation of 2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic AcidMethyl Ester.

[0308] Prepared as in Example I-12. The yield was 3.83 g (37%).

[0309]¹H-NMR (CDCl₃): δ 1.35-1.75 (m, 8H), 2.70-2.90 (m, 1H), 3.80 (s,3H), 4.02 (s, 1H, OH), 6.95-7.05 (m, 1H), 7.10-7.20 (m, 1H), 7.20-7.25(m, 1H).

[0310] (Intermediate I-13 is described in E. Atkinson et al. J. Med.Chem., (1977), Vol 20, No 12, 1612-1617)

[0311] Method -d—

[0312] Intermediate I-14

[0313] Preparation of 2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0314] Cyclopentylmagnesium cloride, 0.0472 mol (23.6 ml of a solution2M in ether) was added to a solution of 9.4 g (0.0377 mol) of2-fur-2-yl-2-oxoacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl esterdissolved in 125 ml of THF, at −70° C. under a N₂ atmosphere. Themixture was stirred at this temperature for 10 minutes, and then warmedto room temperature. After 16 h, the reaction mixture was treated with asaturated solution of ammonium chloride and extracted twice with ethylacetate. The organic phases were combined, washed with water, and driedover MgSO₄. After removal of the solvent, the oil obtained (7.5 g) waspurified by chromatography on silica gel eluting withchloroform/methanol/ammonia 95:5:0.5. Appropiate fractions were combinedand evaporated to obtain the two diastereomers: I-14a, I-14b

[0315] Intermediate I-14a

[0316] (2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0317] 1.55 g of an oil corresponding to the first eluted diastereomerwas triturated with a mixture of isopropyl ether/petroleum ether 1:1, togive 0.24 g (4%, based on single isomer) of a solid whose structure wasconfirmed by ¹H-NMR as a pure diastereomer; mp=109.6-110.6° C.

[0318] [α]²² _(D)=+19.7° (c=1, CHCl₃)

[0319]¹H-NMR (CDCl₃): δ 1.22-1.37 (m, 1H), 1.40-1.80 (m, 11H), 1.97 (m,1H), 2.74-2.96 (m, 6H), 3.19-3.30 (m, 1H), 3.80 (bs, 1H, OH), 4.85-4.89(m, 1H), 6.34-6.37 (m, 2H), 7.35 (m, 1H)

[0320] MS: [M+1]⁺=320.

[0321] Intermediate I-14a was hydrolised (EtOH/NaOH 2N, 2 h r.t.) togive (+)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid: [α]²²_(D)=+31.95° (c=1, EtOH).

[0322] Configuration S was assigned. (See TABLE 1).

[0323] Intermediate I-14b

[0324] (2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0325] 1.10 g of a solid corresponding to the second eluted diastereomerwas triturated with a mixture of isopropyl ether/petroleum ether 1:1, togive 0.42 g (7%, based on single isomer) of a solid whose structure wasconfirmed by ¹H-NMR as a pure diastereomer;

[0326] mp=119.9-122.1° C.

[0327] [α]²² _(D)=−14.2° (c=1, CHCl₃)

[0328]¹H-NMR (CDCl₃): δ 1.40-1.90 (m, 12H), 2.07 (m, 1H), 2.49-2.56 (m,1H), 2.67-2.86 (m, 5H), 3.12-3.24 (m, 1H), 3.80 (bs, 1H, OH), 4.87-4.91(m, 1H), 6.35-6.39 (m, 2H), 7.38 (m, 1H)

[0329] MS: [M+1]⁺=320

[0330] Intermediate I-14b was hydrolised (EtOH/NaOH 2N, 2 h r.t.) togive (−)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid: [α]²²_(D)=−32.10° (c=1, EtOH).

[0331] Configuration R was assigned. (See TABLE 1).

[0332] (2-Fur-2-yl-2-oxoacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-ylester may be prepared as described in WO 01/04118)

[0333] Intermediate I-15

[0334] Preparation of 2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic Acid.(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0335] Prepared using the same method as for Intermediate I-14, but fromfrom 20.8 g (0.0784 mol) of of 2-oxo-2-thien-2-ylacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester and cyclopentylmagnesium cloride,0.08 mol (40 ml of a solution 2M in ether). The oil obtained (15.64 g)was purified by chromatography on silica gel eluting withchloroform/methanol/ammonia 97:3:0.5 to obtain 8.38 g (32%) of a pureproduct, mixture of diastereomers: I-15a and I-15b. Structure confirmedby ¹H-NMR.

[0336] Intermediate I-15a

[0337] (2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0338] The oil mixture of diastereomers was treated with isopropyl etherto obtain a solid, that was treated again with isopropyl ether to yield2.2 g of a pure diastereomer (Intermediate I-15a, 16.7% based on asingle isomer).

[0339] [α]²² _(D)=−5.75° (c=1, CHCl₃); mp: 152-157° C.

[0340]¹H-NMR (CDCl₃): δ 1.40-1.80 (m, 11H), 1.80-2.0 (m, 1H), 2.10 (m,1H), 2.52-2.65 (m, 1H), 2.70-2.95 (m, 5H), 3.10-3.22 (m, 1H), 4.07 (s,1H, OH), 4.85-4.95 (m, 1H), 6.95-7.05 (m, 1H), 7.10-7.20 (m, 1H),7.20-7.27 (m, 1H).

[0341] MS: [M+1]⁺=336

[0342] Intermediate I-15a was hydrolised (EtOH/NaOH 2N, 2 h r.t. and 2 hat 60° C.) to give (−)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid:[α]²² _(D)=−6.44° (c=1, EtOH). Configuration S was assigned. (See TABLE1).

[0343] Intermediate I-15b

[0344] (2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0345] The mother liquors of the first crystallization of intermediateI-15a were evaporated, and the oil obtained treated with isopropyl etherto give a solid, that was treated again with isopropyl ether to yield1.47 g of the second diastereomer Intermediate I-15b (11.2% based onsingle Isomer). [α]²² _(D)=+22.49° (c=1, CHCl₃); mp: 99-102° C.

[0346]¹H-NMR (CDCl₃): δ 1.25-1.85 (m, 12H), 2.0 (m, 1H), 2.65-2.95 (m,6H), 3.22-3.34 (m, 1H), 4.05 (s, 1H, OH), 4.804.92 (m, 1H), 6.90-7.0 (m,1H), 7.10-7.16 (m, 1H), 7.20-7.27 (m, 1H).

[0347] MS: [M+1]⁺=336

[0348] Intermediate I-15b was hydrolised (EtOH/NaOH 2N, 2 h r.t. and 2 hat 60° C.) to give (+)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid:[α]²² _(D)=+6.63° (c=1, EtOH). Configuration R was assigned. (See TABLE1).

[0349] (Intermediates I-15a and I-15b have also been prepared followingmethod c)

[0350] (2-Oxo-2-thien-2-ylacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-ylester may be prepared as described in WO 01/04118)

[0351] Intermediate I-16

[0352] Preparation of 2-Cyclohexyl-2-hydroxy-2-phenylacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0353] Cyclohexylmagnesium cloride, 0.127 mol (63.6 ml of a solution 2Min ether), was added to a solution of 28.7 g (0.111 mol) of2-oxo-2-phenylacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl esterdissolved in 350 ml of THF, at −70° C. under a N₂ atmosphere. Themixture was stirred at this temperature for 10 minutes, and then warmedto room temperature. After 1 h, the reaction mixture was treated with asaturated solution of ammonium chloride and extracted twice with ethylacetate. The organic phases were combined, washed with water, and driedover MgSO₄. After removal of the solvent, the oil obtained (27.0 g) waspurified by chromatography on silica gel eluting withchloroform/methanol 10:1. The yield was 18.7 g (49.2%) of a pureproduct, mixture of diastereomers: I-16a and I-16b.

[0354] Intermediate I-16a

[0355] (2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester

[0356] 16 g of the oil mixture of diastereomers were dissolved inisopropanol and treated with 5.4 g of fumaric acid. After cooling to0-5° C., 8 g of the fumarate salt of the first diastereomer(Intermediate I-16a) were obtained.

[0357] Fumarate salt: MS: [M (free base)+1]⁺=344.

[0358] The 8 g of this salt were recrystallised from isopropanol toobtain 5 g of a more pure product. This salt was treated with CHCl₃ andK₂CO₃ solution to obtain the free base Intermediate I-16a.

[0359] I-16a (Free Base):

[0360] [α]²² _(D)=−14.9° (c=1, CHCl₃).

[0361]¹H-NMR(CDCl₃): δ 1.0-1.95 (m, 14H), 2.04-2.12 (m, 1H), 2.16-2.32(m, 1H), 2.38-2.50 (m, 1H), 2.64-2.96 (m, 4H), 3.04-3.16 (m, 1H),3.70-3.85 (s, 1H, OH), 4.854.90 (m, 1H), 7.25-7.40 (m, 3H), 7.60-7.70(m, 2H).

[0362] Intermediate I-16a (free base) was hydrolised (EtOH/NaOH 2N, 7 hat 60° C.) to give (−)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid as apure enantiomer [α]²² _(D)=−23.6° (c=1.4, EtOH). This value was assignedto the R configuration provided that in the literature (A. Tambuté, A.Collet; Bulletin de la Société Chimique de France, 1984, No 1-2, pagesII-77 to II-82) the (2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid hasbeen described with [α]²² _(D)=+25.2° (c=1.4, EtOH). (See TABLE 1).

[0363] Intermediate I-16b

[0364] (2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester

[0365] The mother liquors of the fumarate salt of the Intermediate I-16awere evaporated and the residue dissolved in water. The obtainedsolution was washed with ether, basified with K₂CO₃ and extracted WithCHCl₃. The organic layer was dried over MgSO₄ and the solvent wasevaporated. The oil obtained (7.5 g) was dissolved in 50 ml ofisopropanol and treated with EtOH/HCl(g). After the addition of 75 ml ofethyl ether, 3.1 g of the chlorhidrate salt of the second diasteroemer,Intermediate I-16b, were obtained.

[0366] Chlorhidrate salt: MS: [M (free base)+1]⁺=344.

[0367] The chlorhidrate salt was treated with CHCl₃ and K₂CO₃ solutionto obtain the free base Intermediate I-16b.

[0368] I-16b (Free Base):

[0369] [α]²² _(D)=+25.3° (c=1, CHCl₃).

[0370]¹H-NMR (CDCl₃): δ 1.0-1.78 (m, 13H), 1.78-1.90 (m, 1H), 1.92-2.0(m, 1H), 2.20-2.34 (m, 1H), 2.66-2.96 (m, 5H), 3.20-3.32 (m, 1H),3.70-3.85 (s, 1H, OH), 4.75-4.85 (m, 1H), 7.25-7.40 (m, 3H), 7.60-7.70(m, 2H).

[0371] Intermediate I-16b (free base) was hydrolised (EtOH/NaOH 2N, 60°C., 8 h) to give (+)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid as apure enantiomer [α]²² _(D)=+23.1° (c=1.4, EtOH). This value was assignedto the S configuration according with the results obtained withIntermediate I-16a. (See TABLE 1).

[0372] (2-Oxo-2-phenylacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl estermay be prepared as described in WO 92/04346.)

[0373] Intermediate I-17

[0374] 2-hydroxy-2,3-diphenylpropionic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester

[0375] Prepared using the same method as for Intermediate I-16 as amixture of diastereomers I-17a and I-17b, which were separated bycrystallisation using ether/isopropyl ether.

[0376] Intermediate I-17a

[0377] (2*)-2-hydroxy-2,3-diphenylpropionic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester, First Diastereomer Obtained.

[0378] The yield was 0.87 g (42.6% based on single isomer), mp: 132° C.

[0379]¹H-NMR (CDCl₃): δ 1.30-1.60 (m, 2H), 1.60-1.90 (m, 2H), 2.05 (m,1H), 2.20-2.35 (m, 1H), 2.50-2.90 (m, 4H), 3.0-3.15 (m, 1H), 3.25 and3.60 (dd, 2H), 3.70 (bs, 1H, OH), 4.704.80 (m, 1H), 7.15-7.45 (m, 8H),7.65-7.75 (m, 2H).

[0380] MS: [M+1]⁺=352

[0381] ((*): Configuration not assigned)

[0382] Intermediate I-17b

[0383] (2*)-2-hydroxy-2,3-diphenylproplonic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester, Second Diastereomer Obtained

[0384] The yield was 0.23 g (11.2% based on single isomer), mp: 107° C.

[0385]¹H-NMR (CDCl₃): δ 1.20-1.35 (m, 1H), 1.35-1.55 (m, 2H), 1.55-1.70(m, 1H), 1.80-1.95 (m, 1H), 2.55-2.90 (m, 5H), 3.10-3.20 (m, 1H), 3.25and 3.60 (dd, 2H), 3.80 (bs, 1H, OH), 4.65-4.80 (m, 1H), 7.20-7.50 (m,8H), 7.65-7.75 (m, 2H).

[0386] MS: [M+1]⁺=352

[0387] ((*): Configuration not assigned)

[0388] Intermediate I-18

[0389] 2-Hydroxy-3-phenyl-2-thien-2-ylpropionic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0390] Prepared using the same method as for Intermediate I-15 as amixture of diastereomers. The yield was 0.81 g (54%). The product waspurified by preparation of the chlorhidrate salt, 0.57 g of this saltwere obtained (63% from the free base).

[0391] Chlorhidrate Salt:

[0392]¹H-NMR (DMSO-d₆): δ 1.40-1.60 (m, 1H), 1.60-1.95 (m, 3H), 2.05 and2.10 (m, 1H), 2.75-3.65 (m, 8H), 4.90-5.05 (m, 1H), 6.50 and 6.55 (s,1H, OH), 6.95-7.05 (m, 1H), 7.10-7.30 (m, 6H), 7.40-7.50 (m, 1H), 10.9(bs, 1H, NH⁺).

[0393] MS: [M+1]⁺=358

[0394] Intermediate I-19

[0395] 2-Hydroxy-2-thien-2-ylpent-3-ynoic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0396] Prepared using the same method as for Intermediate I-15 as amixture of diastereomers. The yield was 1.88 g (25.6%)

[0397]¹H-NMR (CDCl₃): δ 1.20-1.90 (m, 4H), 1.92 and 1.96 (s, 3H, CH3),2.0 and 2.16 (m, 1H), 2.45-2.90 (m, 5H), 3.05-3.20 and 3.15-3.27 (m,1H), 4.85-4.92 (m, 1H), 6.94-7.0 (m, 1H), 7.24-7.30 (m, 2H), the signalfor OH group is observed between 4.5 and 5.5 as a broad band.

[0398] MS: [M+1]⁺=306

[0399] Intermediate I-20.

[0400] 2-Hydroxy-2-thien-2-ylbut-3-enoic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0401] Prepared using the same method as for Intermediate I-15 as amixture of diastereomers. The yield was 1.74 g (18.8%)

[0402]¹H-NMR (CDCl₃): δ 1.30-1.90 (m, 4H), 2.05-2.15 (m, 1H), 2.60-3.0(m, 5H), 3.15-3.35 (m, 1H), 3.40-4.70 (broad band, 1H, OH), 4.85-4.95(m, 1H), 5.30-5.40 (m, 1H), 5.60-5.75 (m, 1H), 6.30-6.50 (m, 1H),6.95-7.05 (1H), 7.10-7.15 (m, 1H), 7.25-7.30 (m, 1H).

[0403] MS: [M+1]⁺=294

[0404] Intermediate I-21

[0405] 2-Hydroxy-4-phenyl-2-thien-2-ylbutyric Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0406] Prepared using the same method as for Intermediate I-15 as amixture of diastereomers. The yield was 0.29 g (2.4%).

[0407]¹H-NMR (CDCl₃): δ 1.25-1.95 (m, 4H), 1.95-2.10 (m, 1H), 2.30-3.0(m, 9H), 3.10-3.25 (m, 1H), 4.80-4.90 (m, 1H), 6.95-7.05 (m, 1H),7.05-7.40 (m, 7H).

[0408] MS: [M+1]⁺=372

[0409] Method -e—

[0410] Intermediate I-22

[0411] Preparation of 2-Hydroxymethyl-2,3-diphenylproplonic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester

[0412] Lithium diisopropylamide (0.0048 mol) 2.40 ml of a 2M solution(in heptane/THF/ethylbenzene) was added to a stirred solution of 1;5 g(0.0045 mol) of 2,3-diphenylpropionic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester in 30 ml of THF at −70° C. undera N₂ atmosphere. CH₂O (gas) was bubbled into the reaction mixture via asteady stream of dry N₂ during 10 min at −70° C. and then while themixture was warmed at room temperature. The reaction was quenched byaddition of saturated ammonium chloride solution (100 ml) and theresultant mixture was extracted twice with 100 ml of ethyl acetate. Theorganic layers were combined, dried over MgSO₄ and evaporated to yield1.9 g of an oil. This 1.9 g were combined with 3.28 g of a previouspreparation and the product obtained (5.18 g) was purified bychromatography on silica gel eluting with chloroform/methanol/ammoniafrom 97.5:2.5:0.25 to 90:10:1. Appropiate fractions were combined andevaporated to obtain the two diastereomers: Intermediates I-22a andI-22b

[0413] Intermediate I-22a:

[0414] (2*)-2-Hydroxymethyl-2,3-diphenylpropionic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0415] 1.25 g of a solid corresponding to the first eluted diastereomerwas triturated with isopropyl ether, to give 0.95 g (42%, based onsingle isomer) of a white solid whose structure was confirmed by ¹H-NMRas a pure diastereomer; mp: 119° C.

[0416]¹H-NMR (CDCl₃): δ 1.20-1.35 (m, 1H), 1.40-1.70 (m, 3H), 1.90 (m,1H), 2.5 (bs, OH), 2.60-2.85 (m, 5H), 3.15-3.25 (m, 1H), 3.40-3.50 (dd,2H), 3.95-4.10 (dd, 2H), 4.85 (m, 1H), 7.05 (m, 2H), 7.15-7.40 (m, 8H)

[0417] MS: [M+1]⁺=366

[0418] ((*): Configuration not assigned)

[0419] Intermediate I-22b

[0420] (2*)-2-Hydroxymethyl-2,3-diphenylpropionic Acid(3R)-1-azabicyclo[2.2.2]oct-3-yl Ester.

[0421] 1.84 g of an oil corresponding to the second eluted diastereomerwas purified by column chromatography (in the above describedconditions) to yield 1.26 g of a solid that after trituration withisopropyl ether yield 0.95 g of a white solid whose structure wasconfirmed by ¹H-NMR as a pure diastereomer (42%, based on singleisomer); mp: 154° C.

[0422] H-NMR (CDCl₃): δ 1.20-1.35 (m, 1H), 1.50-1.75 (m, 3H), 2.0 (m,1H), 2.35 (bs, OH), 2.50-2.80 (m, 5H), 3.10-3.20 (m, 1H), 3.35-3.50 (dd,2H), 3.954.10 (dd, 2H), 4.85 (m, 1H), 7.0 (m, 2H), 7.15-7.40 (m, 8H).

[0423] MS: [M+1]⁺=366

[0424] ((*): Configuration not assigned)

[0425] Also included within the scope of the present invention arepharmaceutical compositions which comprise, as the active ingredient, atleast one quinuclidine derivative of general formula (I) in associationwith a pharmaceutically acceptable carrier or diluent. Preferably thecomposition is made up in a form suitable for oral administration.

[0426] The pharmaceutically acceptable carrier or diluents which aremixed with the active compound or compounds, to form the composition ofthis invention are well-known per se and the actual excipients useddepend inter alia on the intended method of administration of thecomposition.

[0427] Compositions of this invention are preferably adapted for oraladministration. In this case, the composition for oral administrationmay take the form of tablets, film-coated tablets, liquid inhalant,powder inhalant and inhalation aerosol; all containing one or morecompounds of the invention; such preparations may be made by methodswell-known in the art.

[0428] The diluents which may be used in the preparations of thecompositions include those liquid and solid diluents which arecompatible with the active ingredient, together with colouring orflavouring agents, if desired. Tablets or film-coated tablets mayconveniently contain between 1 and 500 mg, preferably from 5 to 300 mgof active ingredient. The inhalant compositions may contain between 1 μgand 1,000 μg, preferably from 10 μg to 800 μg of active ingredient. Inhuman therapy, the dose of the compound of general formula (I) depend onthe desired effect and duration of treatment; adult doses are generallybetween 3 mg and 300 mg per day as tablets and 10 μg and 800 μg per dayas inhalant composition.

[0429] Pharmacological Action

[0430] The results on human muscarinic receptors binding and in the teston bronchospasm in guinea pig, were obtained as described below.

[0431] Human Muscarinic Receptor Studies.

[0432] The binding of [3H]-NMS to human muscarinic receptors wasperformed according to Waelbroek et al (1990), Mol. Pharmacol., 38:267-273. Assays were carried out at 25° C. Membrane preparations fromstably transfected chinese hamster ovary-K1 cells (CHO) expressing thegenes for the human muscarinic receptors M3 were used.

[0433] For determination of IC₅₀, membrane preparations were suspendedin DPBS to a final concentration of 89 μg/ml for the M3 subtype. Themembrane suspension was incubated with the tritiated compound for 60min. After incubation the membrane fraction was separated by filtrationand the bound radioactivity determined. Non specific binding wasdetermined by addition of 10⁻⁴ M atropine. At least six concentrationswere assayed in duplicate to generate individual displacement curves.

[0434] Our results show that the compounds of the present invention havehigh affinities for muscarinic M3 receptors, preferably human muscarinicreceptors. Affinity levels have been measured by in vitro assays asdescribed above at 100 nM and 10 nM. Preferred compounds of theinvention produce an inhibition of [3H]-NMS binding of at least 35% at10 nM and of at least 65% at 100 nM (Table 2). TABLE 2 % INHIBITION %INHIBITION concentration: concentration: N° COMPOUND 1.00E−07 M 1.00E−08M Atropine 88.3 69.75 Ipratropium 93.75 67.25 bromide 13 76 36 14 76.539.0 16 74.2 36.3 22 81.5 72 23 75.6 63.3 24 78 56.6 25 76.1 62.6 2675.6 63.8 28 78.3 60.6 29 79.0 53.8 31 74.3 54.3 32 73.9 44.5 33 72.846.7 34 85.3 68.3 36 84.2 42.0 37 88.1 72.6 38 86.3 57.7 40 86.9 72.7 4383.4 58.7 44 84.6 44.6 46 87.1 57.6 53 81.5 58 54 72.5 44.1 56 77.3 53.857 77.4 47.1 61 75.1 39.9 64 78.6 64.5 65 79.8 66.0 67 75.1 52.5 69 70.843.9 70 71.2 50.0 80 72.4 55.8 81 70.1 45.4 82 70.6 55.3 83 72.7 60.3 8468.3 41.0 86 68.2 37.2 88 65.5 35.7 89 68.5 51.3 92 69.4 49.2

[0435] Test on Bronchospasm in Guinea Pig

[0436] The studies were performed according to H. Konzett and F. Rössler(1940), Arch. Exp. Path. Pharmacol. 195: 71-74. Aqueous solutions of theagents to be tested were nebulized and inhaled by anaesthetizedventilated male guinea pigs (Dunkin-Hartley). Bronchial response tointravenous acetylcholine challenge was determined before and after drugadministration and the changes in pulmonary resistance at severaltime-points were expressed as percent of inhibition of bronchoespasm.

[0437] The compounds of the present invention inhibited the bronchospasmresponse to acetylcholine with high potency and a long duration ofaction.

[0438] From the above described results one of ordinary skill in the artcan readily understand that the compounds of the present invention haveexcellent antimuscarinic activity (M3) and thus are useful for thetreatment of diseases in which the muscarinic M3 receptor is implicated,including respiratory disorders such as chronic obstructive pulmonarydisease (COPD), bronchitis, bronchial hyperreactivity, asthma, cough andrhinitis; urological disorders such as urinary incontinence,pollakiuria, neurogenic or unstable bladder, cystospasm and chroniccystitis; gastrointestinal disorders such as irritable bowel syndrome;spastic colitis, diverticulitis and peptic ulceration; andcardiovascular disorders such as vagally induced sinus bradycardia. Forexample, the compounds of the present invention are useful for thetreatment of respiratory diseases such as chronic obstructive pulmonarydisease, chronic bronchitis, asthma, and rhinitis; urinary diseases suchas urinary incontinence and pollakinuria in neuripenia pollakinuria,neurogenic bladder, nocturnal enuresis, unstable bladder, cytospasm andchronic cystitis; and gastrointestinal diseases such as irritable bowelsyndrome, spastic colitis and diverticulitis.

[0439] The present invention further provides a compound of formula (I)or a pharmaceutically acceptable composition comprising a compound offormula (I) for use in a method of treatment of the human or animal bodyby therapy, in particular for the treatment of respiratory, urologicalor gastrointestinal disease or disorder.

[0440] The present invention further provides the use of a compound offormula (I) or a pharmaceutically acceptable composition comprising acompound of formula (I) for the manufacture of a medicament for thetreatment of a respiratory, urological or gastrointestinal disease ordisorder.

[0441] Further, the compounds of formula (I) and pharmaceuticalcompositions comprising a compound of formula (I) can be used in amethod of treating a respiratory, urological or gastrointestinal diseaseor disorder, which method comprises administering to a human or animalpatient in need of such treatment an effective, non-toxic, amount of acompound of formula (I) or a pharmaceutical composition comprising acompound of formula (I).

[0442] Further, the compounds of formula (I) and pharmaceuticalcompositions comprising a compound of formula (I) can be used incombination with other drugs effective in the treatment of thesediseases. For example with 52 agonists, steroids, antiallergic drugs,phosphodiesterase IV inhibitors and/or leukotriene D4 (LTD4) inhibitors,for simultaneous, separate or sequential use in the treatment of arespiratory disease.

[0443] The present invention therefore further provides a combinationproduct comprising

[0444] (i) a compound according to the invention; and

[0445] (ii) another compound effective in the treament of a respiratory,urological or gastrointestinal disease or disorder

[0446] for simultaneous, separate or sequential use.

[0447] The compound (ii) which is effective in the treament of arespiratory, urological or gastrointestinal disease or disorder may be a52 agonist, steroid, antiallergic drug, phosphodiesterase IV inhibitorand/or leukotriene D4 (LTD4) antagonist when the product is forsimultaneous, separate or sequential use in the treatment of arespiratory disease. Alternatively, the compound (ii) may be a 2agonist, steroid, antiallergic drug, and/or phosphodiesterase IVinhibitor when the product is for simultaneous, separate or sequentialuse in the treatment of a respiratory disease.

[0448] The present invention will be further illustrated by thefollowing examples. The examples are given by way of illustration onlyand are not to be construed as limiting.

EXAMPLE 1

[0449](3R)-3-(2,3-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate.

[0450] The title compound was synthesised as a mixture of diastereomersaccording to methods c, and b from the Intermediate I-2. The yield ofthe final step was 20 mg, 71%.

[0451] MS [M-CF₃COO]⁺: 470.

[0452]¹H-NMR (DMSO-d₆): δ 1.50-1.72 (m, 2H), 1.75-1.95 (m, 2H),1.97-2.15 (m, 3H), 2.95-3.15 (m, 4H), 3.20-3.50 (m, 5H), 3.75-3.85 (m,1H), 3.95-4.15 (m, 3H), 4.95-5.05 (m, 1H), 6.90-7.0 (m, 4H), 7.15-7.45(m, 11H).

EXAMPLE 2

[0453](3R)-3-(2,3-Diphenylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0454] The title compound was synthesised as a mixture of diastereomersaccording to methods c, and b from the Intermediate I-2. The yield ofthe final step was 15 mg, 55%.

[0455] MS [M-CF₃COO]⁺: 460.

[0456]¹H-NMR (DMSO-d₆): δ 1.50-1.70 (m, 2H), 1.70-2.0 (m, 4H), 2.0-2.15(m, 1H), 2.75-2.85 (m, 2H), 2.85-3.20 (m, 4H), 3.20-3.45 (m, 5H),3.70-3.82 (m, 1H), 4.024.12 (m, 1H), 4.95-5.02 (m, 1H), 6.90-7.05 (m,2H), 7.10-7.45 (m, 11H)

EXAMPLE 3

[0457](3R)-3-[(2*)-2-Hydroxymethyl-2,3-diphenylproplonyloxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (diastereomer 1)

[0458] The title compound was synthesised according to methods e, and bfrom the Intermediate I-22a. The yield of the final step was 15 mg, 52%.

[0459] MS [M-CF₃COO]⁺: 490.

[0460]¹H-NMR (DMSO-d₆): δ 1.55-1.75 (m, 2H), 1.75-2.05 (m, 4H), 2.21 (m,1H), 2.75-2.85 (m, 2H), 2.85-2.95 (m, 1H), 3.05-3.45 (m, 8H), 3.75-3.87(m, 2H), 3.92-4.0 (m, 1H), 5.08 (m, 1H), 5.20-5.23 (t, 1H, OH),6.82-6.90 (m, 2H), 6.90-6.95 (m, 1H), 6.95-7.02 (m, 1H), 7.05-7.20 (m,5H), 7.20-7.35 (m, 3H), 7.37-7.42 (m, 1H).

EXAMPLE 4

[0461](3R)-3-[(2*)-2-Hydroxymethyl-2,3-diphenylproponyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate (Diastereomer 1)

[0462] The title compound was synthesised according to methods e, and bfrom the Intermediate I-22a. The yield of the final step was 18 mg, 64%.

[0463] MS [M-CF₃COO]⁺: 470.

[0464]¹H-NMR (DMSO-d₆): δ 1.62-1.75 (m, 2H), 1.80-2.05 (m, 2H), 2.26 (m,1H), 2.90-3.12 (m, 3H), 3.20-3.55 (m, 8H), 3.80-4.02 (m, 3H), 5.10-5.17(m, 1H), 5.20-5.25 (t, 1H, OH); 6.82-6.90 (m, 2H), 7.10-7.20 (m, 5H),7.22-7.40 (m, 8H).

EXAMPLE 5

[0465](3R)-3-[(2*)-2-Hydroxymethyl-2,3-diphenylpropionyloxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate (Diastereomer 2)

[0466] The title compound was synthesised according to methods e, and bfrom the Intermediate I-22b. The yield of the final step was 10.1 mg,37.5%.

[0467] MS [M-CF₃COO]⁺: 490.

[0468]¹H-NMR (DMSO-d₆): δ 1.45-1.60 (m, 1H), 1.60-1.75 (m, 1H),1.80-2.05 (m, 4H), 2.18 (m, 1H), 2.75-2.90 (m, 2H), 2.95-3.10 (m, 1H),3.10-3.55 (m, 8H), 3.75-3.92 (m, 2H), 4.0-4.12 (m, 1H), 5.05-5.15 (m,1H), 5.25-5.35 (t, 1H, OH), 6.70-6.85 (m, 2H), 6.90-7.20 (m, 7H),7.20-7.35 (m, 3H), 7.35-7.42 (m, 1H).

EXAMPLE 6

[0469](3R)-3-[(2*)-2-Hydroxymethyl-2,3-diphenylpropionyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate (Diastereomer 2)

[0470] The title compound was synthesised according to methods e, and bfrom the Intermediate I-22b. The yield of the final step was 22 mg, 76%.

[0471] MS [M-CF₃COO]⁺: 470.

[0472]¹H-NMR (DMSO-d₆): δ 1.50-1.60 (m, 1H), 1.60-1.80 (m, 1H),1.85-2.05 (m, 2H), 2.21 (m, 1H), 2.90-3.10 (m, 2H), 3.12-3.55 (m, 9H),3.78-3.83 (m, 1H), 3.88-3.95 (m, 1H), 4.07-4.12 (m, 1H), 5.15-5.20 (m,1H), 5.35-5.40 (t, 1H, OH), 6.75-6.80 (m, 2H), 7.07.15 (m, 3H),7.20-7.40 (m, 8H).

EXAMPLE 7

[0473](3R)-3-[(2*)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneBromide (Diastereomer 1)

[0474] The title compound was synthesised according to methods d, and afrom the Intermediate I-17a. The yield of the final step was 380 mg,96%.

[0475] MS [M-Br]⁺: 486, mp: 1.03° C.

[0476]¹H-NMR (DMSO-d₆): δ 1.65-1.75 (m, 2H), 1.75-2.02 (m, 2H),2.02-2.15 (m, 2H), 2.24 (m, 1H), 3.05-3.25 (m, 2H), 3.25-3.55 (m, 7H),3.78-3.90 (m, 1H), 3.98-4.08 (m, 2H), 5.02-5.10 (m, 1H), 6.20 (s, 1H,OH), 6.92-7.0 (m, 3H), 7.10-7.22 (m, 5H), 7.25-7.40 (m, 5H), 7.52-7.58(m, 2H).

EXAMPLE 8

[0477](3R)-3-[(2*)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octaneBromide (Diastereomer 1)

[0478] The title compound was synthesised according to methods d, and afrom the Intermediate I-17a. The yield of the final step was 320 mg,83%.

[0479] MS [M-Br]⁺: 472, mp: 223° C.

[0480]¹H-NMR (DMSO-d₆): δ 1.70-1.80 (m, 2H), 1.80-2.0 (m, 2H), 2.20 (m,1H), 3.15-3.55 (m, 7H), 3.55-3.70 (m, 2H), 3.85-4.0 (m, 1H), 4.304.45(m, 2H), 5.0-5.10 (m, 1H), 6.10 (s, 1H, OH), 6.90-7.05 (m, 3H),7.05-7.20 (m, 5H), 7.20-7.40 (m, 5H), 7.45-7.55 (m, 2H).

EXAMPLE 9

[0481](3R)-3-(2*)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate (Diastereomer 2) The title compound was synthesisedaccording to methods d, and b from the Intermediate I-17b. The yield ofthe final step was 7.2 mg, 25%.

[0482] MS [M-CF₃COO]⁺: 486.

[0483]¹H-NMR (DMSO-d₆): δ 1.40-1.55 (m, 1H), 1.55-1.70 (m, 1H), 1.75-2.0(m, 2H), 2.11 (m, 3H), 3.10-3.60 (m, 9H), 3.77-3.87 (m, 1H), 4.0-4.1 (m,2H), 5.0-5.1 (m, 1H), 6.14 (s, 1H, OH), 6.90-7.0 (m, 3H), 7.15-7.25 (m,5H), 7.25-7.42 (m, 5H), 7.60-7.67 (m, 2H).

EXAMPLE 10

[0484](3R)-3-[(2*)-2-Hydroxy-2,3-diphenylpropionyloxy-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate (Diastereomer 2)

[0485] The title compound was synthesised according to methods d, and bfrom the Intermediate I-17b. The yield of the final step was 5.4 mg,19%.

[0486] MS [M-CF₃COO]⁺: 472.

[0487]¹H-NMR (DMSO-d₆): δ 1.40-1.55 (m, 1H), 1.55-1.70 (m, 1H), 1.80-2.6(m, 2H), 2.12 (m, 1H), 3.20-3.60 (m, 7H), 3.60-3.70 (m, 2H), 3.90-4.0(m, 1H), 4.42 (m, 2H), 5.0-5.1 (m, 1H), 6.15 (s, 1H, OH), 6.95-7.05 (m,3H), 7.10-7.22 (m, 5H), 7.25-7.40 (m, 5H), 7.57-7.65 (m, 2H).

EXAMPLE 11

[0488](3R)-3-(2-Hydroxy-3-phenyl-2-thien-2-ylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0489] The title compound was synthesised as a mixture of diastereomersaccording to methods d, and b from Intermediate I-18. The yield of thefinal step was 15 mg, 52%.

[0490] MS [M-CF₃COO]⁺: 492.

[0491]¹H-NMR (DMSO-d₆): δ 1.45-1.70 (m, 1H), 1.75-2.0 (m, 3H), 2.0-2.30(m, 3H), 3.0-3.17 (m, 1H), 3.17-3.57 (m, 8H), 3.80-3.90 (m, 1H),3.97-4.10 (m, 2H), 5.02-5.05 (m, 1H), 6.52-6.60 (d, 1H, OH), 6.90-7.04(m, 4H), 7.14-7.28 (m, 6H), 7.28-7.38 (m, 2H), 7.42-7.50 (m, 1H).

EXAMPLE 12

[0492](3R)-3-(2-Hydroxy-3-phenyl-2-thien-2-ylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0493] The title compound was synthesised as a mixture of diastereomersaccording to methods d, and b from Intermediate I-18. The yield of thefinal step was 21 mg, 74%.

[0494] MS [M-CF₃COO]⁺: 482

[0495]¹H-NMR (DMSO-d₆): δ 1.45-1.70 (m, H), 1.75-2.05 (m, 5H), 2.05-2.3(m, 1H), 2.77-2.87 (m, 2H), 2.90-3.10 (m, 1H), 3.10-3.52 (m, 8H),3.75-3.82 (m, 1H), 5.0-5.07 (m, 1H), 6.52-6.57 (d, 1H, OH), 6.92-7.05(m, 3H), 7.10-7.27 (m, 6H), 7.37-7.47 (m, 2H).

EXAMPLE 13

[0496](3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneBromide

[0497] The title compound was obtained as a mixture of diastereomersaccording to methods C, and a from Intermediate I-3. The yield of thefinal step was 300 mg, 71%.

[0498] MS [M-Br]⁺: 442, mp: 157°, (described in experimental section,method a)

[0499]¹H-NMR (DMSO-d₆): δ 1.70-2.05 (m, 4H), 2.05-2.35 (m, 3H),2.70-2.83 (m, 1H), 2.90-3.02 (m, 1H), 3.25-3.60 (m, 7H), 3.82-3.97 (m,1H), 3.974.10 (m, 2H), 5.05-5.25 (m, 3H), 5.70-5.90 (m, 1H), 6.50 (d,1H, OH), 6.90-7.05 (m, 4H), 7.10-7.20 (m, 1H), 7.27-7.35 (m, 2H), 7.45(m, 1H).

EXAMPLE 14

[0500](3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0501] The title compound was obtained as a mixture of diastereomersaccording to methods c, and b from Intermediate I-3. The yield of thefinal step was 10 mg, 39.3%.

[0502] MS [M-CF₃COO]⁺: 432.

[0503]¹H-NMR (DMSO-d₆): δ 1.65-2.18 (m, 6H), 2.18-2.30 (m, 1H),2.70-3.05 (m, 4H), 3.10-3.55 (m, 4H), 3.55-3.68 (m, 1H), 3.78-3.92 (m,2H), 4.0-4.1 (m, 1H), 5.0-5.20 (m, 3H), 5.70-5.85 (m, 1H), 6.48-6.52 (d,1H, OH), 6.90-7.02 (m, 3H), 7.10-7.20 (m, 1H), 7.35-7.42 (m, 1H),7.42-7.50 (m, 1H).

EXAMPLE 15

[0504](3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octaneBromide

[0505] The title compound was obtained as a mixture of diastereomersaccording to methods c, and a from Intermediate I-3. The yield of thefinal step was 270 mg, 66%.

[0506] MS [M-Br]⁺: 428, mp: 82° C.

[0507]¹H-NMR (DMSO-d₆): δ 1.72-2.10 (m, 4H), 2.20-2.35 (m, 1H),2.70-2.85 (m, 1H), 2.90-3.05 (m, 1H), 3.25-3.85 (m, 7H), 3.92-4.12 (m,1H), 4.35-4.45 (m, 2H), 4.95-5.20 (m, 3H), 5.70-5.90 (m, 1H), 6.50 (s,1H, OH), 6.90-7.05 (m, 4H), 7.10-7.18 (m, 1H), 7.25-7.45 (m, 3H).

EXAMPLE 16

[0508](3R)-3-(2-Hydroxy-2-thien-2-ylheptanoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0509] The title compound was obtained as a mixture of diastereomersaccording to methods c, and b from Intermediate I-1. The yield of thefinal step was 16.2 mg, 57%.

[0510] MS [M-CF₃COO]⁺: 472.

[0511]¹H-NMR (DMSO-d₆): δ 0.80-0.90 (m, 3H), 1.15-1.40 (m, 6H),1.65-2.30 (m, 9H), 3.20-3.60 (m, 5H), 3.85-3.95 (m, 1H), 3.95-4.10 (m,2H), 5.05-5.17 (m, 1H), 6.30-6.35 (d, 1H, OH), 6.90-7.05 (m, 4H),7.10-7.17 (m, 1H), 7.25-7.35 (m, 2H), 7.42-7.48 (m, 1H).

EXAMPLE 17

[0512](3R)-3-(2-Hydroxy-2-thien-2-ylheptanoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate.

[0513] The title compound was obtained as a mixture of diastereomersaccording to methods c, and b from Intermediate I-1. The yield of thefinal step was 6.8 mg, 12%.

[0514] MS [M-CF₃COO]⁺: 462.

[0515]¹H-NMR (DMSO-d₆): δ 0.80-0.90 (m, 3H), 1.15-1.40 (m, 6H),1.65-2.30 (m, 9H), 2.80-2.85 (m, 2H), 3.10-3.55 (m, 7H), 3.75-3.90 (m,1H), 5.10 (m, 1H), 6.30-6.32 (d, 1H, OH), 6.90-6.95 (m, 1H), 6.95-7.02(m, 2H), 7.09-7.13 (m, 0.1H), 7.37-7.39 (m, 1H), 7.40-7.45 (m, 1H).

EXAMPLE 18

[0516](3R)-3-(2-Hydroxy-2-thien-2-ylpent-3-ynoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0517] The title compound was obtained as a mixture of diastereomersaccording to methods d, and b from Intermediate I-19. The yield of thefinal step was 6.4 mg, 12%.

[0518] MS [M-CF₃COO]⁺: 440.

[0519]¹H-NMR (DMSO-d₆): δ 1.60-2.05 (m, 7H), 2.05-2.20 (m, 2H),2.20-2.35 (m, 1H), 3.10-3.60 (m, 7H), 3.82-3.97 (m, 1H), 3.974.10 (m,2H), 5.13 (m, 1H), 6.90-7.06 (m, 4H), 7.20-7.38 (m, 4H), 7.50-7.56 (m,1H).

EXAMPLE 19

[0520](3R)-3-(2-Hydroxy-2-thien-2-ylpent-3-ynoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0521] The title compound was obtained as a mixture of diastereomersaccording to methods d, and b from Intermediate I-19. The yield of thefinal step was 2.4 mg, 4.3%.

[0522] MS [M-CF₃COO]⁺: 430

[0523]¹H-NMR (DMSO-d₆): δ 1.60-2.10 (m, 9H), 2.20-2.35 (m, 1H),2.75-2.90 (m, 2H), 3.10-3.70 (m, 7H), 3.75-3.95 (m, 1H), 5.12 (m, 1H),6.91-7.04 (m, 3H), 7.19-7.42 (m, 3H), 7.48-7.55 (m, 1H).

EXAMPLE 20

[0524](3R)-3-(2-Hydroxy-2-thien-2-ylbut-3-enoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0525] The title compound was obtained as a mixture of diastereomersaccording to methods d, and b from Intermediate I-20. The yield of thefinal step was 9.6 mg, 16%.

[0526] MS [M-CF₃COO]⁺: 428

[0527]¹H-NMR (DMSO-d₆): δ 1.60-2.05 (m, 4H), 2.05-2.20 (m, 2H),2.20-2.38 (m, 1H), 3.15-3.60 (m, 7H), 3.82-3.95 (m, 1H), 3.98-4.10 (m,2H), 5.10-5.20 (m, 1H), 5.25-5.35 (m, 1H), 5.45-5.55 (m, 1H), 6.45-6.55(m, 1H), 6.75-6.82 (d, 1H, OH), 6.92-6.96 (m, 3H), 6.98-7.03 (m, 1H),7.13-7.15 (m, 1H), 7.28-7.34 (m, 1H), 7.48-7.52 (m, 1H).

EXAMPLE 21

[0528](3R)-3-(2-Hydroxy-2-thien-2-ylbut-3-enoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0529] The title compound was obtained as a mixture of diastereomersaccording to methods d, and b from Intermediate I-20. The yield of thefinal step was 5.8 mg, 10%.

[0530] MS [M-CF₃COO]⁺: 418

[0531]¹H-NMR (DMSO-d₆): δ 1.60-2.20 (m, 6H), 2.20-2.35 (m, 1H),2.79-2.84 (m, 2H), 3.10-3.55 (m, 7H), 3.80-3.90 (m, 1H), 5;10-5.20 (m,1H), 5.25-5.35 (m, 1H), 5.45-5.55 (m, 1H), 6.45-6.55 (m, 1H), 6.75-6.78(d, 1H, OH), 6.92-6.95 (m, 1H), 6.95-7.05 (m, 2H), 7.10-7.15 (m, 1H),7.35-7.42 (m, 1H), 7.45-7.52 (m, 1H).

EXAMPLE 22

[0532](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneBromide

[0533] The title compound was synthesised according to methods d, and afrom the Intermediate I-15a. The yield of the final step was 230 mg,85%.

[0534] MS [M-Br]⁺: 470, mp: 171° C.

[0535]¹H-NMR (DMSO-d₆): δ 1.27-1.67 (m, 8H), 1.8-2.05 (m, 4H), 2.05-2.20(m, 2H), 2.25-2.35 (m, 1H), 2.70-2.92 (m, 1H), 3.20-3.25 (m, 1H),3.25-3.60 (m, 6H), 3.80-3.95 (m, 1H), 3.95-4.08 (m, 2H), 5.10-5.20 (m,1H), 6.18 (s, 1H, OH), 6.87-7.05 (m, 4H), 7.08-7.20 (m, 1H), 7.25-7.37(m, 2H), 7.40-7.47 (m, 1H).

EXAMPLE 23

[0536](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-yl-acetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0537] The title compound was synthesised according to methods d, and bfrom the Intermediate I-15a. The yield of the final step was 21 mg, 75%.

[0538] MS [M-CF₃COO]⁺: 460

[0539]¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.80-2.10 (m, 6H), 2.28 (m,1H), 2.75-2.85 (m, 3H), 3.10-3.55 (m, 7H), 3.80-3.90 (m, 1H), 5.05-5.15(m, 1H), 6.20 (s, 1H, OH), 6.90-6.95 (m, 1H), 6.95-7.05 (m, 2H),7.10-7.20 (m, 1H), 7.35-7.45 (m, 2H).

EXAMPLE 24

[0540](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octaneBromide

[0541] The title compound was synthesised according to methods c, and afrom the Intermediate I-15a. The yield of the final step was 338 mg,92%.

[0542] MS [M-Br]⁺: 456; mp: 75° C.

[0543]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.10 (m, 4H),2.27-2.35 (m, 1H), 2.70-2.90 (m, 1H), 3.30-3.68 (m, 5H), 3.68-3.83 (m,2H), 3.92-4.10 (m, 1H), 4.32-4.50 (m, 2H), 5.10-5.20 (m, 1H), 6.20 (s,1H, OH), 6.90-7.05 (m, 4H), 7.10-7.20 (m, 1H), 7.30-7.42 (m, 3H).

EXAMPLE 25

[0544](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0545] The title compound was synthesised as in Example 23. The yield ofthe final step was 17 mg, 64%.

[0546] MS [M-CF₃COO]⁺: 440

[0547]¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.80-2.10 (m 4H), 2.32 (m,1H), 2.75-2.85 (m, 1H), 2.95-3.05 (m, 2H), 3.20-3.50 (m, 6H), 3.50-3.65(m, 1H), 3.85-3.95 (m, 1H), 5.10-5.20 (m, 1H), 6.22 (s, 1H, OH),6.95-7.05 (m, 1H), 7.10-7.20 (m, 1H), 7.20-7.40 (m, 5H), 7.40-7.55 (m,1H)

EXAMPLE 26

[0548](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0549] The title compound was synthesised as in Example 23. The yield ofthe final step was 20 mg, 74%.

[0550] MS [M-CF₃COO]⁺: 454

[0551]¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.75-2.05 (m, 6H), 2.28 (m,1H), 2.55-2.65 (m, 2H), 2.75-2.85 (m, 1H), 3.10-3.40 (m, 6H), 3.40-3.55(m, 1H), 3.77-3.87 (m, 1H), 5.05-5.15 (m, 1H), 6.20 (s, 1H, OH),6.95-7.0 (m, 1H), 7.10-7.15 (m, 1H), 7.20-7.35 (m, 5H), 7.38-7.42 (m,1H).

EXAMPLE 27

[0552](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0553] The title compound was synthesised as in Example 23. The yield ofthe final step was 3 mg, 12%.

[0554] MS [M-CF₃COO]⁺: 452

[0555]¹H-NMR (DMSO-d₆): δ 1.25-1.60 (m, 8H), 1.80-2.10 (m, 4H), 2.31 (m,1H), 2.72-2.85 (m, 1H), 3.12-3.22 (m, 1H), 3.22-3.45 (m, 3H), 3.45-3.60(m, 1H), 3.82-3.92 (m, 1H), 3.95-4.10 (m, 2H), 5.10-5.20 (m, 1H), 6.20(s, 1H, OH), 6.35-6.50 (m, 1H), 6.82-6.95 (m, 2H), 7.10-7.15 (m, 1H),7.25-7.47 (m, 4H), 7.55-7.62 (m, 2H).

EXAMPLE 28

[0556](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0557] The title compound was synthesised as in Example 23. The yield ofthe final step was 15 mg, 52%.

[0558] MS [M-CF₃COO]⁺: 488

[0559]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.80-2.05 (m, 4H),2.05-2.17 (m, 2H), 2.30 (m, 1H), 2.75-2.90 (m, 1H), 3.17-3.27 (m, 1H),3.27-3.60 (m, 6H), 3.82-3.95 (m, 1H), 3.97-4.05 (m, 2H), 5.14 (m, 1H),6.22 (s, 1H, OH), 6.92-7.05 (m, 3H), 7.10-7.20 (m, 3H), 7.40-7.55 (m,1H).

EXAMPLE 29

[0560](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetdxy]-1-(4-oxo-4-thien-2-ylbutyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0561] The title compound was synthesised as in Example 23. The yield ofthe final step was 4 mg, 14%.

[0562] MS [M-CF₃COO]⁺: 488

[0563]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.70-2.05 (m, 6H), 2.30 (m,1H), 2.75-2.90 (m, 1H), 3.05-3.12 (m, 2H), 3.15-3.60 (m, 7H), 3.80-3.92(m, 1H), 5.13 (m, 1H), 6.22 (s, 1H, OH), 6.98-7.02 (m, 1H), 7.12-7.18(m, 1H), 7.25-7.30 (m, 1H), 7.40-7.55 (m, 1H), 7.95-8.0 (m, 1H),8.02-8.07 (m, 1H).

EXAMPLE 30

[0564](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[4-(4-fluorophenyl)-4oxobutyl]-1-azoniabicyclo[2.2.2]octane Trifluoroacetate

[0565] The title compound was synthesised as in Example 23. The yield ofthe final step was 9 mg, 29%.

[0566] MS [M-CF₃COO]⁺: 500

[0567]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.05 (m, 6H), 2.30 (m,1H), 2.75-2.90 (m, 1H), 3.05-3.60 (m, 9H), 3.80-3.95 (m, 1H), 5.14 (m,1H), 6.22 (s, 1H, OH), 6.98-7.02 (m, 1H), 7.12-7.20 (m, 1H), 7.35-7.45(m, 3H), 8.02-8.12 (m, 2H).

EXAMPLE 31

[0568](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0569] The title compound was synthesised as in Example 23. The yield ofthe final step was 14 mg, 48%.

[0570] MS [M-CF₃COO]⁺: 486

[0571]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.80-2.0 (m, 4H), 2.0-2.20(m, 2H), 2.30 (m, 1H), 2.75-2.90 (m, 1H), 3.17-3.25 (m, 1H), 3.25-3.60(m, 6H), 3.82-3.92 (m, 1H), 3.94-4.02 (m, 2H), 5.14 (m, 1H), 6.21 (s,1H, OH), 6.30-6.42 (m, 3H), 6.95-7.10 (m, 2H), 7.12-7.20 (m, 1H),7.20-7.45 (m, 1H), 9.47 (s, 1H, OH).

EXAMPLE 32

[0572]1-(2-Benzyloxyethyl)-(3R)-3-(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0573] The title compound was synthesised as in Example 23. The yield ofthe final step was 10 mg, 35%.

[0574] MS [M-CF₃COO]⁺: 470

[0575]¹H-NMR (DMSO-d₆): δ 1.25-1.62 (m, 8H), 1.80-2.07 (m, 4H), 2.30 (m,1H), 2.75-2.85 (m, 1H), 3.0-3.65 (m, 7H), 3.75-4.0 (m, 3H), 4.50 (s,2H), 5.10-5.17 (m, 1H), 6.21 (s, 1H, OH), 6.95-7.0 (m, 1H), 7.10-7.17(m, 1H), 7.27-7.45 (m, 6H).

EXAMPLE 33

[0576](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-o-tolyloxypropyl)1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0577] The title compound was synthesised as in Example 23. The yield ofthe final step was 13 mg, 45%.

[0578] MS [M-CF₃COO]⁺: 484

[0579]¹H-NMR (DMSO-d₆): δ 1.23-1.65 (m, 8H), 1.80-2.05 (m, 4H),2.05-2.20 (m, 5H), 2.31 (m, 1H), 2.75-2.90 (m, 1H), 3.15-3.25 (m, 1H),3.27-3.60 (m, 6H), 3.85-3.95 (m, 1H), 3.97-4.05 (m, 2H), 5.15 (m, 1H),6.22 (s, 1H, OH), 6.83-6.93 (m, 2H), 6.98-7.02 (m, 1H), 7.12-7.20 (m,3H), 7.40-7.46 (m, 1H).

EXAMPLE 34

[0580]1-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0581] The title compound was synthesised as in Example 23. The yield ofthe final step was 11 mg, 32%.

[0582] MS [M-CF₃COO]⁺: 495

[0583]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.05 (m, 4H),2.05-2.20 (m, 2H), 2.30 (m, 1H), 2.75-2.90 (m, 1H), 3.20-3.25 (m, 1H),3.25-3.60 (m, 6H), 3.82-3.95 (m, 1H), 4.05-4.15 (m, 2H), 5.07-5.20 (m,1H), 6.20 (s, 1H, OH), 6.95-7.05 (m, 1H), 7.12-7.20 (m, 1H), 7.25-7.35(m, 1H), 7.40-7.57 (m, 4H)

EXAMPLE 35

[0584](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[13-(naphthalen-1-yloxy)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0585] The title compound was synthesised as in Example 23. The yield ofthe final step was 10 mg, 26%.

[0586] MS [M-CF₃COO]⁺: 520, (described in experimental section, methodb).

[0587]¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.80-2.10 (m, 4H),2.20-2.37 (m, 3H), 2.75-2.92 (m, 1H), 3.20-3.65 (m, 7H), 3.90-4.05 (m,1H), 4.15-4.30 (m, 2H), 5.15-5.22 (m, 1H), 6.24 (s, 1H, OH), 6.95-7.05(m, 2H), 7.15-7.20 (m, 1H), 7.40-7.60 (m, 5H), 7.85-7.95 (m, 1H),8.20-8.25 (m, 1H)

EXAMPLE 36

[0588](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(methylphenylamino)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0589] The title compound was synthesised as in Example 23. The yield ofthe final step was 12 mg, 35%.

[0590] MS [M-CF₃COO]⁺: 483

[0591]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.02 (m, 6H), 2.28 (m,1H), 2.75-2.85 (m, 1H), 2.87 (s, 3H), 3.09-3.14 (m, 1H), 3.15-3.55 (m,8H), 3.75-3.87 (m, 1H), 5.05-5.15 (m, 1H), 6.20 (s, 1H, OH), 6.60-6.70(m, 1H), 6.70-6.77 (m, 2H), 6.92-7.0 (m, 1H), 7.10-7.25 (m, 3H),7.35-7.45 (m, 1H).

EXAMPLE 37

[0592](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0593] The title compound was synthesised as in Example 23. The yield ofthe final step was 7 mg, 22%.

[0594] MS [M-CF₃COO]⁺: 486

[0595]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.02 (m, 6H), 2.27 (m,1H), 2.75-2.90 (m, 1H), 2.95-3.05 (m, 2H), 3.07-3.15 (m, 1H), 3.15-3.52(m, 6H), 3.75-3.87 (m, 1H), 5.05-5.15 (m, 1H), 6.20 (s, 1H, OH),6.95-7.0 (m, 1H), 7.12-7.17 (m, 1H), 7.20-7.30 (m, 1H), 7.30-7.45 (m,5H).

EXAMPLE 38

[0596](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0597] The title compound was synthesised as in Example 23. The yield ofthe final step was 9 mg, 26%.

[0598] MS [M-CF₃COO]⁺: 482

[0599]¹H-NMR (DMSO-d₆): δ 1.30-1.67 (m, 8H), 1.72-2.10 (m, 6H), 2.30 (m,1H), 2.75-2.90 (m, 1H), 3.10-3.60 (m, 9H), 3.85-3.95 (m, 1H), 5.10-5.20(m, 1H), 6.23 (s, 1H, OH), 6.95-7.05 (m, 1H), 7.12-7.20 (m, 1H),7.40-7.47 (m, 1H), 7.52-7.60 (m, 2H), 7.62-7.72 (m, 1H), 7.95-8.05 (m,1H).

EXAMPLE 39

[0600](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(2,4,6-trimethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0601] The title compound was synthesised as in Example 23. The yield ofthe final step was 13 mg, 35%.

[0602] MS [M-CF₃COO]⁺: 512

[0603]¹H-NMR (DMSO-d₆): δ 61.30-1.65 (m, 8H), 1.80-2.02 (m, 4H),2.02-2.25 (m, 11H), 2.32 (m, 1H), 2.75-2.90 (m, 1H), 3.23-3.28 (m, 1H),3.28-3.62 (m, 6H), 3.65-3.80 (m, 2H), 3.85-3.97 (m, 1H), 5.10-5.20 (m,1H), 6.22 (s, 1H, OH), 6.82 (s, 2H), 6.97-7.05 (m, 1H), 7.12-7.20 (m,1H), 7.40-7.47 (m, 1H)

EXAMPLE 40

[0604] ylacetoxy]-1-azoniabicyclo[2.2.2]octane Trifluoroacetate

[0605] The title compound was synthesised as in Example 23. The yield ofthe final step was 13 mg, 36%.

[0606] MS [M-CF₃COO]⁺: 505

[0607]¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.75-2.05 (m, 4H),2.05-2.25 (m, 2H), 2.31 (m, 1H), 2.75-2.90 (m, 1H), 3.19-3.23 (m, 1H),3.23-3.62 (m, 6H), 3.854.0 (m, 1H), 4.07-4.15 (m, 2H), 5.10-5.20 (m,1H), 6.22 (s, 1H, OH), 6.92-7.05 (m, 2H), 7.12-7.22 (m, 2H), 7.27-7.37(m, 1H), 7.40-7.50 (m, 2H).

EXAMPLE 41

[0608](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(3-trifluoromethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0609] The title compound was synthesised as in Example 23. The yield ofthe final step was 13 mg, 33%.

[0610] MS [M-CF₃COO]⁺: 538

[0611]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.05 (m, 4H),2.05-2.25 (m, 2H), 2.31 (m, 1H), 2.75-2.90 (m, 1H), 3.20-3.25 (m, 1H),3.25-3.62 (m, 6H), 3.82-3.97 (m, 1H), 4.05-4.20 (m, 2H), 5.10-5.20 (m,1H), 6.22 (s, 1H, OH), 6.95-7.05 (m, 1H), 7.12-7.20 (m, 1H), 7.22-7.30(m, 2H), 7.30-7.37 (m, 1H), 7.40-7.47 (m, 1H), 7.50-7.62 (m, 1H).

EXAMPLE 42

[0612]1-[3-(Biphenyl-4-yloxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0613] The title compound was synthesised as in Example 23. The yield ofthe final step was 11 mg, 30%.

[0614] MS [M-CF₃COO]⁺: 546

[0615]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.77-2.05 (m, 4H),2.05-2.25 (m, 2H), 2.31 (m, 1H), 2.75-2.92 (m, 1H), 3.20-3.23 (m, 1H),3.23-3.62 (m, 6H), 3.85-3.97 (m, 1H), 4.05-4.15 (m, 2H), 5.10-5.20 (m,1H), 6.22 (s, 1H, OH), 6.95-7.10 (m, 3H), 7.12-7.20 (m, 1H), 7.27-7.37(m, 1H), 7.40-7.50 (m, 3H), 7.55-7.70 (m, 4H).

EXAMPLE 43

[0616](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(2,4-difluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0617] The title compound was synthesised as in Example 23. The yield ofthe final step was 10 mg, 28%.

[0618] MS [M-CF₃COO]⁺: 506

[0619]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.05 (m, 4H),2.05-2.15 (m, 2H), 2.30 (m, 1H), 2.82 (m, 1H), 3.17-3.28 (m, 1H),3.28-3.47 (m, 5H), 3.47-3.60 (m, 1H), 3.82-3.95 (m, 1H), 4.05-4.15 (m,2H), 5.14 (m, 1H), 6.22 (s, 1H, OH), 6.95-7.10 (m, 2H), 7.12-7.38 (m,3H), 7.40-7.45 (m, 1H).

EXAMPLE 44

[0620](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0621] The title compound was synthesised as in Example 23. The yield ofthe final step was 11 mg, 32%.

[0622] MS [M-CF₃COO]⁺: 500

[0623]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.15 (m, 6H), 2.30 (m,1H), 2.82 (m, 1H), 3.18-3.25 (m, 1H), 3.25-3.45 (m, 5H), 3.45-3.60 (m,1H), 3.70 (s, 3H), 3.82-3.92 (m, 1H), 3.92-4.02 (m, 2H), 5.14 (m, 1H),6.22 (s, 1H, OH), 6.88 (m, 4H), 6.98-7.02 (m, 1H), 7.15-7.16 (m, 1H),7.42-7.44 (m, 1H).

EXAMPLE 45

[0624](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0625] The title compound was synthesised as in Example 23. The yield ofthe final step was 14 mg, 38%.

[0626] MS [M-CF₃COO]⁺: 524

[0627]¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.65-1.75 (m, 4H),1.75-2.20 (m, 6H), 2.30 (m, 1H), 2.50-2.70 (m, 4H), 2.75-2.95 (m, 1H),3.17-3.25 (m, 1H), 3.25-3.45 (m, 5H), 3.45-3.60 (m, 1H), 3.80-3.92 (m,1H), 3.92-4.02 (m, 2H), 5.14 (m, 1H), 6.22 (s, 1H, OH), 6.60-6.70 (m,2H), 6.95-7.02 (m, 2H), 7.15-7.20 (m, 1H), 7.42-7.45 (m, 1H).

EXAMPLE 46

[0628]1-[3-(Benzo[1,3]dioxol-5-yloxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0629] The title compound was synthesised as in Example 23. The yield ofthe final step was 13 mg, 38%.

[0630] MS [M-CF₃COO]⁺: 514

[0631]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.15 (m, 6H), 2.30 (m,1H), 2.75-2.90 (m, 1H), 3.15-3.25 (m, 1H), 3.25-3.42 (m, 5H), 3.42-3.60(m, 1H), 3.82-3.92 (m, 1H), 3.92-4.0 (m, 2H), 5.13 (m, 1H), 5.97 (s,2H), 6.20 (s, 1H, OH), 6.36-6.40 (m, 1H), 6.64-6.65 (m, 1H), 6.81-6.84(m, 1H), 6.98-7.02 (m, 1H), 7.15-7.17 (m, 1H), 7.42-7.44 (m, 1H).

EXAMPLE 47

[0632]1-[3-(2-Carbamoyl-phenoxy)-propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-yl-acetoxy]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0633] The title compound was synthesised as in Example 23. The yield ofthe final step was 13 mg, 36%.

[0634] MS [M-CF₃COO]⁺: 513

[0635]¹H-NMR (DMSO-d₆): δ 1.27.1.65 (m, 8H), 1.80-2.07 (m, 4H),2.12-2.27 (m, 2H), 2.31 (m, 1H), 2.82 (m, 1H), 3.17-3.25 (m, 1H),3.25-3.45 (m, 5H), 3.45-3.60 (m, 1H), 3.82-3.92 (m, 1H), 4.10-4.17 (m,2H), 5.15 (m, 1H), 6.23 (s, 1H, OH), 6.98-7.16 (m, 4H), 7.42-7.50 (m,2H), 7.50-7.55 (bs, 2H), 7.68-7.72 (m, 1H).

EXAMPLE 48

[0636](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(3-dimethylaminophenoxy)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0637] The title compound was synthesised as in Example 23. The yield ofthe final step was 14 mg, 40%.

[0638] MS [M-CF₃COO]: 513

[0639]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.70-2.20 (m, 6H), 2.30 (m,1H), 2.75-2.95 (m, 7H), 3.15-3.65 (m, 7H), 3.80-4.05 (m, 3H), 5.14 (m,1H), 6.15-6.30 (m, 3H), 6.32-6.36 (m, 1H), 6.95-7.22 (m, 3H), 7.40-7.45(m, 1H).

EXAMPLE 49

[0640]1-[3-(4-Acetylaminophenoxy)propyl]-(3R)-3-[(2)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0641] The title compound was synthesised as in Example 23. The yield ofthe final step was 12 mg, 34%.

[0642] MS [M-CF₃COO]⁺: 527

[0643]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m. 8H), 1.75-2.20 (m, 9H), 2.30 (m,1H), 2.82 (m, 1H), 3.17-3.28 (m, 1H), 3.28-3.45 (m, 5H), 3.45-3.60 (m,1H), 3.84-3.92 (m, 1H), 3.96-4.02 (m, 2H), 5.13 (m, 1H), 6.22 (s, 1H,OH), 6.86-6.90 (m, 2H), 6.98-7.02 (m, 1H), 7.15-7.17 (m, 1H), 7.42-7.44(m, 1H), 7.48-7.52 (m, 2H), 9.85 (s, 1H, NH(CO)).

EXAMPLE 50

[0644](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-methoxycarbonylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0645] The title compound was synthesised as in Example 23. The yield ofthe final step was 14 mg, 37%.

[0646] MS [M-CF₃COO]⁺: 528

[0647]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.80-2.05 (m, 4H),2.05-2.25 (m, 2H), 2.31 (m, 1H), 2.82 (m, 1H), 3.17-3.28 (m, 1H),3.28-3.45 (m, 5H), 3.45-3.60 (m, 1H), 3.82 (s, 3H), 3.82-3.95 (m, 1H),4.10-4.15 (m, 2H), 5.14 (m, 1H), 6.22 (s, 1H, OH), 6.95-7.10 (m, 3H),7.15-7.17 (m, 1H), 7.43-7.45 (m, 1H), 7.92-7.97 (m, 2H).

EXAMPLE 51

[0648](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0649] The title compound was synthesised as in Example 23. The yield ofthe final step was 15 mg, 41%.

[0650] MS [M-CF₃COO]⁺: 515

[0651]¹H-NMR (DMSO-d₆): δ 1.27-1.65 (m, 8H), 1.77-2.07 (m, 4H),2.10-2.27 (m, 2H), 2.31 (m, 1H), 2.82 (m, 1H), 3.17-3.28 (m, 1H),3.28-3.45 (m, 5H), 3.45-3.60 (m, 1H), 3.85-3.95 (m, 1H), 4.15-4.25 (m,2H), 5.15 (m, 1H), 6.22 (s, 1H, OH), 6.97-7.02 (m, 1H), 7.14-7.18 (m,3H), 7.42-7.45 (m, 1H), 8.22-8.27 (m, 2H).

EXAMPLE 52

[0652](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0653] The title compound was synthesised as in Example 23. The yield ofthe final step was 13 mg, 36%.

[0654] MS [M-CF₃COO]⁺: 500

[0655]¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.77-2.05 (m, 4H),2.05-2.20 (m, 2H), 2.30 (m, 1H), 2.82 (m, 1H), 3.17-3.60 (m, 7H),3.82-3.95 (m, 1H), 3.95-4.05 (m, 2H), 4.35-4.45 (m, 2H), 5.05-5.11 (t,1H, OH), 5.11-5.20 (m, 1H), 6.22 (s, 1H, OH), 6.86-6.95 (m, 2H),6.95-7.05 (m, 1H), 7.15-7.17 (m, 1H), 7.22-7.26 (m, 2H), 7.42-7.44 (m,1H).

EXAMPLE 53

[0656](3R)-3-[(2R)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneBromide

[0657] The title compound was synthesised according to methods d, and afrom the Intermediate I-15b. The yield of the final step was 1.2 g(73%).

[0658] mp: 181° C. MS: [M-Br]⁺: 470.

[0659]¹H-NMR (DMSO-d₆): δ 1.30-1.70 (m, 8H), 1.70-1.80 (m, 2H),1.80-2.05 (m, 2H), 2.05-2.30 (m, 3H), 2.80-2.95 (m, 1H), 3.25-3.62 (m,7H), 3.87-4.0 (m, 1H), 4.0-4.10 (m, 2H), 5.10-5.20 (m, 1H), 6.20 (s, 1H,OH), 6.95-7.05 (m, 4H), 7.15-7.25 (m, 1H), 7.25-7.37 (m, 2H), 7.42-7.45(m, 1H).

EXAMPLE 54

[0660](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0661] The title compound was synthesised according to methods d, and bfrom the Intermediate I-15b. The yield of the final step was 15 mg(54%).

[0662] MS [M-CF₃COO]⁺: 460

[0663]¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m 8H), 1.65-1.80 (m, 2H), 1.80-2.10(m, 4H), 2.21 (m, 1H), 2.77-2.90 (m, 3H), 3.15-3.40 (m, 6H), 3.40-3.55(m, 1H), 3.80-3.92 (m, 1H), 5.05-5.18 (m, 1H), 6.20 (s, 1H, OH),6.92-6.96 (m, 1H), 6.96-7.02 (m, 2H), 7.12-7.20 (m, 1H), 7.36-7.40 (m,1H), 7.40-7.46 (m, 1H)

EXAMPLE 55

[0664](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0665] The title compound was synthesised as in Example 54. The yield ofthe final step was 16 mg, 58%.

[0666] MS [M-CF₃COO]⁺: 456.

[0667]¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.75-1.85 (m, 2H),1.85-2.05 (m, 2H), 2.23 (m, 1H), 2.75-2.90 (m; 1H), 3.40-3.57 (m, 4H),3.57-3.70 (m, 1H), 3.70-3.80 (m, 2H), 3.97-4.10 (m, 1H), 4.374.47 (m,2H), 5.10-5.18 (m, 1H), 6.20 (s, 1H, OH), 6.92-7.05 (m, 4H), 7.10-7.18(m, 1H), 7.30-7.38 (m, 2H), 7.38-7.44 (m, 1H),

EXAMPLE 56

[0668](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0669] The title compound was synthesised as in Example 54. The yield ofthe final step was 13 mg, 50%.

[0670] MS [M-CF₃COO]⁺: 440.

[0671]¹H-NMR (DMSO-d₆): δ 1.35-1.65 (m, 8H), 1.65-1.85 (m, 2H),1.85-2.05 (m, 2H), 2.25 (m, 1H), 2.85-2.92 (m, 1H), 2.95-3.10 (m, 2H),3.30-3.50 (m, 6H), 3.50-3.65 (m, 1H), 3.85-4.0 (m, 1H), 5.12-5.20 (m,1H), 6.21 (s, 1H, OH), 6.95-7.05 (m, 1H), 7.15-7.20 (m, 1H), 7.25-7.40(m, 5H), 7.40-7.47 (m, 1H).

EXAMPLE 57

[0672](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0673] The title compound was synthesised as in Example 54. The yield ofthe final step was 14 mg, 53%.

[0674] MS [M-CF₃COO]⁺: 454.

[0675]¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.65-1.77 (m, 2H),1.77-2.05 (m, 4H), 2.21 (s, 1H), 2.55-2.65 (m, 2H), 2.75-2.92 (m, 1H),3.15-3.40 (m, 6H), 3.40-3.55 (m, 1H), 3.80-3.90 (m, 1H), 5.06-5.16 (m,1H), 6.19 (s, 1H, OH), 6.95-7.02 (m, 1H), 7.12-7.18 (m, 1H), 7.20-7.36(m, 5H), 7.38-7.46 (m, 1H).

EXAMPLE 58

[0676](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0677] The title compound was synthesised as in Example 54. The yield ofthe final step was 7 mg, 26%.

[0678] MS [M-CF₃COO]⁺: 452.

[0679]¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.75-2.05 (m, 4H), 2.24 (m,1H), 2.75-2.90 (m, 1H), 3.25-3.45 (m, 4H), 3.45-3.55 (m, 1H), 3.72-3.95(m, 1H), 4.04.15 (m, 2H), 5.10-5.17 (m, 1H), 6.19 (s, 1H, OH), 6.40-6.55(m, 1H), 6.82-6.70 (m, 2H), 7.12-7.17 (m, 1H), 7.30-7.45 (m, 4H),7.55-7.62 (m, 2H)

EXAMPLE 59

[0680](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0681] The title compound was synthesised as in Example 54. The yield ofthe final step was 19 mg, 64%.

[0682] MS [M-CF₃COO]⁺: 488.

[0683]¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.65-1.80 (m, 2H),1.80-2.05 (m, 2H), 2.05-2.20 (m, 2H), 2.23 (m, 1H), 2.80-2.95 (m, 1H),3.20-3.60 (m, 7H), 3.85-3.95 (m, 1H), 3.97-4.07 (m, 2H), 5.14 (m, 1H),6.20 (s, 1H, OH), 6.90-7.05 (m, 3H), 7.10-7.20 (m, 3H), 7.40-7.47 (m,1H).

EXAMPLE 60

[0684](3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0685] The title compound was synthesised acording to methods d, and bfrom Intermediate I-14a. The yield of the final step was 4 mg, 15%.

[0686] MS [M-CF₃COO]⁺: 454

[0687]¹H-NMR (DMSO-d): δ 1.45-1.67 (m, 9H), 1.67-1.80 (m, 1H), 1.80-2.05(m, 2H), 2.05-2.22 (m, 3H), 2.85-2.95 (m, 1H), 3.20-3.55 (m, 7H),3.85-3.95 (m, 1H), 4.04.10 (m, 2H), 5.10-5.20 (m, 1H), 6.03 (s, 1H),6.40-6.45 (m, 2H), 6.90-7.0 (m, 3H), 7.27-7.35 (m, 2H), 7.62 (m, 1H)

EXAMPLE 61

[0688](3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0689] The title compound was synthesised as in Example 60. The yield ofthe final step was 2 mg, 7%.

[0690] MS [M-CF₃COO]⁺: 444

[0691]¹H-NMR (DMSO-d₆): δ 1.40-1.66 (m, 9H), 1.66-2.10 (m, 5H), 2.17 (m,1H), 2.78-2.90 (m, 3H), 3.14-3.50 (m, 7H), 3.80-3.90 (m, 1H), 5.10-5.18(m, 1H), 6.02 (s, 1H), 6.38-6.46 (m, 2H), 6.92-7.02 (m, 2H), 7.36-7.40(m, 1H), 7.60 (m, 1H).

EXAMPLE 62

[0692](3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0693] The title compound was synthesised as in Example 60. The yield ofthe final step was 4 mg, 17%.

[0694] MS [M-CF₃COO]⁺: 424

[0695]¹H-NMR (DMSO-d₆): δ 1.40-2.05 (m, 12H), 2.20 (m, 1H), 2.88 (m,1H), 2.95-3.05 (m, 2H), 3.20-3.60 (m, 7H), 3.85-3.95 (m, 1H), 5.18 (m,1H), 6.03 (s, 1H, OH), 6.40-6.45 (m, 2H), 7.25-7.40 (m, 5H), 7.62 (m,1H).

EXAMPLE 63

[0696](3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0697] The title compound was synthesised as in Example 60. The yield ofthe final step was 10 mg, 36.2%.

[0698] MS [M-CF₃COO]⁺: 438

[0699]¹H-NMR (DMSO-d₆): δ 1.35-2.05 (m, 14H), 2.16 (m, 1H), 2.55-2.65(m, 2H), 2.75-2.95 (m, 1H), 3.10-3.55 (m, 7H), 3.77-3.92 (m, 1H),5.05-5.15 (m, 1H), 6.02 (s, 1H, OH), 6.35-6.45 (m, 2H), 7.17-7.40 (m,5H), 7.60 (m, 1H).

EXAMPLE 64

[0700](3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0701] The title compound was synthesised acording to methods d, and bfrom Intermediate I-14b. The yield of the final step was 12 mg, 46%.

[0702] MS [M-CF₃COO]⁺: 454

[0703]¹H-NMR (DMSO-d₆): δ 1.40-1.60 (m, 8H), 1.75-2.05 (m, 4H),2.05-2.20 (m, 2H), 2.30 (m, 1H), 2.75-2.87 (m, 1H), 3.10-3.60 (m, 7H),3.85-3.95 (m, 1H), 3.97-4.07 (m, 2H), 5.10-5.17 (m, 1H), 6.04 (s, 1H),6.40-6.50 (m, 2H), 6.90-7.0 (m, 3H), 7.27-7.37 (m, 2H), 7.60-7.65 (m,1H).

EXAMPLE 65

[0704](3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hygroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0705] The title compound was synthesised as In Example 64. The yield ofthe final step was 14 mg, 55%.

[0706] MS [M-CF₃COO]⁺: 444

[0707]¹H-NMR (DMSO-d₆): δ 1.40-1.65 (m, 8H), 1.75-2.10 (m, 6H), 2.27 (m,1H), 2.70-2.90 (m, 3H), 3.0-3.55 (m, 7H), 3.77-3.82 (m, 1H), 5.05-5.15(m, 1H), 6.03 (s, 1H), 6.40-6.45 (m, 2H), 6.90-7.05 (m, 2H), 7.35-7.42(m, 1H), 7.55-7.65 (m, 1H).

EXAMPLE 66

[0708](3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0709] The title compound was synthesised as in Example 64. The yield ofthe final step was 15 mg, 57%.

[0710] MS [M-CF₃COO]⁺: 424

[0711]¹H-NMR (DMSO-d₆): δ 1.30-2.40 (m, 13H), 2.75-2.85 (m, 1H),2.95-3.05 (m, 2H), 3.10-3.75 (m, 7H), 3.85-4.0 (m, 1H), 5.05-5.15 (m,1H), 6.02 (s, 1H, OH), 6.44 (m, 2H), 7.20-7.40 (m, 5H), 7.63 (m, 1H).

EXAMPLE 67

[0712](3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0713] The title compound was synthesised as in Example 64. The yield ofthe final step was 10 mg, 38%.

[0714] MS [M-CF₃COO]⁺: 438

[0715]¹H-NMR (DMSO-d₆): δ 1.40-1.60 (m, 8H), 1.75-2.05 (m, 6H), 2.27 (m,1H), 2.55-2.60 (m, 2H), 2.79 (m, 1H), 3.04-3.10 (m, 1H), 3.12-3.40 (m,5H), 3.40-3.52 (m, 1H), 3.80-3.90 (m, 1H), 5.10 (m, 1H), 6.02 (s, 1H,OH), 6.40 (m, 2H), 7.20-7.35 (m, 5H), 7.58 (m, 1H)

EXAMPLE 68

[0716](3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0717] The title compound was synthesised according to methods d, and bfrom the Intermediate I-16a. The yield of the final step was 28 mg,100%.

[0718] MS [M-CF₃COO]⁺: 478.

[0719]¹H-NMR (DMSO-d₆): δ 0.95-1.18 (m, 4H), 1.18-1.65 (m, 5H),1.70-2.05 (m, 5H), 2.05-2.17 (m, 2H), 2.17-2.30 (m, 2H), 3.15-3.25 (m,1H), 3.25-3.55 (m, 6H), 3.75-3.90 (m, 1H), 3.95-4.07 (m, 2H), 5.05-5.15(m, 1H), 5.78 (s, 1H, OH), 6.90-7.0 (m, 3H), 7.25-7.45 (m, 5H),7.55-7.65 (m, 2H).

EXAMPLE 69

[0720](3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0721] The title compound was synthesised as in Example 68. The yield ofthe final step was 22 mg, 78%.

[0722] MS [M-CF₃COO]⁺: 468.

[0723]¹H-NMR (DMSO-d₆): δ 0.95-1.18 (m, 4H), 1.18-1.65 (m, 5H), 1.70-2.0(m, 7H), 2.20 (m, 2H), 2.75-2.85 (m, 2H), 3.05-3.15 (m, 1H), 3.15-3.50(m, 6H), 3.70-3.85 (m, 1H), 5.05-5.15 (m, 1H), 5.76 (s, 1H, OH),6.90-7.05 (m, 2H), 7.20-7.45 (m, 4H), 7.55-7.65 (m, 2H)

EXAMPLE 70

[0724](3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0725] The title compound was synthesised as in Example 68. The yield ofthe final step was 14 mg, 50%.

[0726] MS [M-CF₃COO]⁺: 448.

[0727]¹H-NMR (DMSO-d₆): δ 0.97-1.15 (m, 3H), 1.15-2.05 (m, 11H),2.15-2.30 (m, 2H), 2.90-3.05 (m, 2H), 3.20-3.30 (m, 1H), 3.30-3.50 (m,5H), 3.50-3.62 (m, 1H), 3.82-3.92 (m, 1H), 5.15 (m, 1H), 5.78 (s, 1H,OH), 7.25-7.45 (m, 8H), 7.58-7.64 (m, 2H).

EXAMPLE 71

[0728](3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0729] The title compound was synthesised according to methods d, and bfrom the Intermediate I-16b. The yield of the final step was 18 mg, 63%.

[0730] MS [M-CF₃COO]⁺: 478.

[0731]¹H-NMR (DMSO-d₆): δ 0.95-1.17 (m, 4H), 1.20-2.0 (m, 10H),2.02-2.35 (m, 4H), 3.15-3.55 (m, 7H), 3.80-3.90 (m, 1H), 3.97-4.10 (m,2H), 5.05-5.15 (m, 1H), 5.75 (s, 1H, OH), 6.90-7.02 (m, 3H), 7.25-7.45(m, 5H), 7.57-7.67 (m, 2H)

EXAMPLE 72

[0732](3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0733] The title compound was synthesised as in Example 71. The yield ofthe final step was 19 mg, 66%.

[0734] MS [M-CF₃COO]⁺: 468.

[0735]¹H-NMR (DMSO-d₆): δ 0.95-1.17 (m, 4H), 1.20-2.10 (m, 12H),2.15-2.35 (m, 2H), 2.75-2.97 (m, 2H), 3.10-3.37 (m, 6H), 3.37-3.55 (m,1H), 3.75-3.87 (m, 1H), 5.05-5.12 (m, 1H), 5.74 (s, 1H, OH), 6.90-7.05(m, 2H), 7.22-7.45 (m, 4H), 7.55-7.67 (m, 2H).

EXAMPLE 73

[0736](3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0737] The title compound was synthesised as in Example 71. The yield ofthe final step was 16 mg, 58%.

[0738] MS [M-CF₃COO]⁺: 448.

[0739]¹H-NMR (DMSO-d₆): δ 0.98-1.15 (m, 3H), 1.20-2.05 (m, 11H),2.20-2.35 (m, 2H), 2.90-3.10 (m, 2H), 3.20-3.50 (m, 6H), 3.50-3.60 (m,1H), 3.80-3.92 (m, 1H), 5.12 (m, 1H), 5.75 (s, 1H, OH), 7.25-7.40 (m,8H), 7.60-7.65 (m, 1H).

EXAMPLE 74

[0740](3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0741] The title compound was synthesised according to methods c, and bfrom the intermediate I-4a. The yield of the final step was 3.8 mg,6.2%.

[0742] MS [M-CF₃COO]⁺: 468.

[0743]¹H-NMR (DMSO-d₆): δ 1.0-1.50 (m, 7H), 1.50-2.05 (m, 7H), 2.05-2.35(m, 4H), 3.15-3.65 (m, 7H), 3.82-3.95 (m, 1H), 4.0-4.1 (m, 2H), 5.16 (m,1H), 5.99 (s, 1H, OH), 6.40-6.45 (m, 2H), 6.90-7.0 (m, 3H), 7.25-7.35(m, 2H), 7.64 (m, 1H).

EXAMPLE 75

[0744](3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0745] The title compound was synthesised as in Example 74. The yield ofthe final step was 3.6 mg, 6%.

[0746] MS [M-CF₃COO]⁺: 458.

[0747]¹H-NMR (DMSO-d₆): δ 1.0-1.45 (m, 7H), 1.50-2.10 (m, 9H), 2.15-2.30(m, 2H), 2.75-2.90 (m, 2H), 3.10-3.55 (m, 7H), 3.77-3.92 (m, 1H), 5.13(m, 1H), 5.98 (s, 1H, OH), 6.36-6.46 (m, 2H), 6.92-7.02 (m, 2H),7.36-7.40 (m, 1H), 7.62 (m, 1H).

EXAMPLE 76

[0748](3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0749] The title compound was synthesised as in Example 74. The yield ofthe final step was 2.4 mg, 4.2%.

[0750] MS [M-CF₃COO]⁺: 438.

[0751]¹H-NMR (DMSO-d₆): δ 1.0-1.45 (m, 7H), 1.50-2.05 (m, 7H), 2.20-2.35(m, 2H), 2.92-3.15 (m, 2H), 3.20-3.65 (m, 7H), 3.85-3.95 (m, 1H), 5.18(m, 1H), 6.0 (s, 1H, OH), 6.37-6.47 (m, 2H), 7.25-7.45 (m, 5H), 7.64 (m,1H).

EXAMPLE 77

[0752](3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0753] The title compound was synthesised as in Example 74. The yield ofthe final step was 2.8 mg, 4.8%.

[0754] MS [M-CF₃COO]⁺: 452.

[0755]¹H-NMR (DMSO-d₆): δ 0.95-1.50 (m, 7H), 1.50-2.10 (m, 9H),2.15-2.32 (m, 2H), 2.55-2.65 (m, 2H), 3.10-3.60 (m, 7H), 3.77-3.80 (m,1H), 5.12 (m, 1H), 5.98 (s, 1H, OH), 6.36-6.46 (m, 2H), 7.18-7.40 (m,5H), 7.62 (m, 1H).

EXAMPLE 78

[0756](3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0757] The title compound was synthesised according to methods c, and bfrom the Intermediate I-4b. The yield of the final step was 3.0 mg, 5%.

[0758] MS [M-CF₃COO]⁺: 468.

[0759]¹H-NMR (DMSO-d₆): δ 1.0-1.45 (m, 7H), 1.55-1.75 (m, 3H), 1.80-2.05(m, 4H), 2.05-2.25 (m, 3H), 2.30 (m, 1H), 3.10-3.20 (m, 1H), 3.20-3.60(m, 6H), 3.85-3.95 (m, 1H), 3.95-4.10 (m, 2H), 5.16 (m, 1H), 5.99 (s.1H, OH), 6.40-6.50 (m, 2H), 6.90-7.0 (m, 3H), 7.25-7.38 (m, 2H), 7.64(m, 1H).

EXAMPLE 79

[0760](3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0761] The title compound was synthesised as In Example 78. The yield ofthe final step was 9.1 mg, 33.1%.

[0762] MS [M-CF₃COO]⁺: 458.

[0763]¹H-NMR (DMSO-d₆): δ 0.95-1.55 (m, 7H), 1.55-2.10 (m, 9H),2.10-2.40 (m, 2H), 2.75-2.95 (m, 2H), 3.0-3.12 (m, 1H), 3.12-3.70 (m,6H), 3.80-3.95 (m, 1H), 5.14 (m, 1H), 6.0 (s, 1H, OH), 6.35-6.55 (m,2H), 6.90-7.10 (m, 2H), 7.35-7.45 (m, 1H), 7.60-7.70 (m, 1H).

EXAMPLE 80

[0764](3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0765] The title compound was synthesised as in Example 78. The yield ofthe final step was 3.6 mg, 6%.

[0766] MS [M-CF₃COO]⁺: 438.

[0767]¹H-NMR (DMSO-d₈): δ 1.0-1.45 (m, 7H), 1.55-1.80 (m, 3H), 1.80-2.10(m, 4H), 2.12-2.28 (m, 1H), 2.30 (m, 1H), 2.90-3.05 (m, 2H), 3.15-3.25(m, 1H), 3.25-3.50 (m, 5H), 3.50-3.65 (m, 1H), 3.85-3.95 (m, 1H), 5.18(m, 1H), 6.0 (s, 1H, OH), 6.38-6.48 (m, 2H), 7.24-7.40 (m, 5H), 7.65 (m,1H).

EXAMPLE 81

[0768](3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0769] The title compound was synthesised as in Example 78. The yield ofthe final step was 5.8 mg, 10%.

[0770] MS [M-CF₃COO]⁺: 452.

[0771]¹H-NMR (DMSO-d₆): δ 1.0-1.42 (m, 7H), 1.55-1.77 (m, 3H), 1.77-2.05(m, 6H), 2.18 (m, 1H), 2.27 (m, 1H), 2.55-2.65 (m, 2H), 3.02-3.12 (m,1H), 3.12-3.60 (m, 6H), 3.77-3.90 (m, 1H), 5.13 (m, 1H), 5.98 (s, 1H,OH), 6.40 (m, 2H), 7.20-7.35 (m, 5H), 7.61 (m, 1H).

EXAMPLE 82

[0772](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0773] The title compound was synthesised according to methods c, and bfrom Intermediate I-5a. The yield of the final step was 9.4 mg, 15.6%.

[0774] MS [M-CF₃COO]⁺: 464

[0775]¹H-NMR (DMSO-d₆): δ 1.10-1.70 (m, 8H), 1.70-2.02 (m, 4H),2.05-2.15 (m, 2H), 2.24 (m, 1H), 2.90-2.97 (m, 1H), 3.15-3.25 (m, 1H),3.25-3.60 (m, 6H), 3.75-3.92 (m, 1H), 3.95-4.10 (m, 2H), 5.10 (m, 1H),5.86 (s, 1H, OH), 6.90-7.0 (m, 3H), 7.20-7.40 (m, 5H), 7.56-7.66 (m,2H).

EXAMPLE 83

[0776](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0777] The title compound was synthesised as in Example 82. The yield ofthe final step was 5.0 mg, 8.8%.

[0778] MS [M-CF₃COO]⁺: 434

[0779]¹H-NMR (DMSO-d₆): δ 1.12-1.70 (m, 8H), 1.75-2.05 (m, 4H), 2.26 (m,1H), 2.87-3.05 (m, 3H), 3.15-3.62 (m, 7H), 3.80-3.92 (m, 1H), 5.13 (m,1H), 5.86 (s, 1H, OH), 7.24-7.44 (m 8H), 7.56-7.66 (m, 2H).

EXAMPLE 84

[0780](3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0781] The title compound was synthesised as in Example 82. The yield ofthe final step was 3.2 mg, 5.1%.

[0782] MS [M-CF₃COO]⁺: 480

[0783]¹H-NMR (DMSO-d₆): δ 1.12-1.65 (m, 8H), 1.65-2.0 (m, 6H), 2.21 (m,1H), 2.85-3.15 (m, 4H), 3.15-3.55 (m, 6H), 3.70-3.85 (m, 1H), 5.06 (m,1H), 5.83 (s, 1H, OH), 7.20-7.46 (m, 8H), 7.54-7.64 (m, 2H).

EXAMPLE 85

[0784] (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane Trifluoroacetate

[0785] The title compound was synthesised according to methods c, and bfrom Intermediate I-5b. The yield of the final step was 7.8 mg, 12.9%.

[0786] MS [M-CF₃COO]⁺: 464

[0787]¹H-NMR (DMSO-d₆): δ 1.15-1.35 (m, 2H), 1.35-2.0 (m, 10H), 2.0-2.30(m, 3H), 2.95-3.10 (m, 1H), 3.20-3.60 (m, 7H), 3.80-3.95 (m, 1H),3.97-4.10 (m, 2H), 5.09 (m, 1H), 5.84 (s, 1H, OH), 6.90-7.0 (m, 3H),7.24-7.44 (m, 5H), 7.60-7.70 (m, 2H).

EXAMPLE 86

[0788](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0789] The title compound was synthesised as in Example 85. The yield ofthe final step was 5.2 mg, 9.2%.

[0790] MS [M-CF₃COO]⁺: 434

[0791]¹H-NMR (DMSO-d₆): δ 1.12-1.32 (m, 2H), 1.32-2.05 (m, 10H), 2.20(m, 1H), 2.90-3.10 (m, 3H), 3.20-3.62 (m, 7H), 3.82-3.97 (m, 1H), 5.12(m, 1H), 5.85 (s, 1H, OH), 7.22-7.45 (m, 8H), 7.60-7.70 (m, 2H).

EXAMPLE 87

[0792](3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0793] The title compound was synthesised as in Example 85. The yield ofthe final step was 4.0 mg, 6.4%.

[0794] MS [M-CF₃COO]⁺: 480

[0795]¹H-NMR (DMSO-d₆): δ 1.12-1.32 (m, 2H), 1.32-1.70 (m, 8H), 1.70-2.0(m, 4H), 2.16 (m, 1H), 2.92-3.05 (m, 3H), 3.15-3.60 (m, 7H), 3.75-3.87(m, 1H), 5.04 (m, 1H), 5.82 (s, 1H, OH), 7.20-7.44 (m, 8H), 7.58-7.68(m, 2H).

EXAMPLE 88

[0796](3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0797] The title compound was synthesised according to methods c, and bfrom intermediate I-6a. The yield of the final step was 3.2 mg, 5.1%.

[0798] MS [M-CF₃COO]⁺: 484

[0799]¹H-NMR (DMSO-d₆): δ 1.0-1.45 (m, 7H), 1.55-1.80 (m, 3H), 1.80-2.20(m, 7H), 2.25-2.35 (m, 1H), 3.20-3.28 (m, 1H), 3.28-3.42 (m, 5H),3.42-3.55 (m, 1H), 3.85-3.95 (m, 1H), 4.014.05 (m, 2H), 5.17 (m, 1H),6.16 (s, 1H, OH), 6.92-7.03 (m, 4H), 7.13-7.15 (m, 1H), 7.28-7.34 (m,2H), 7.42-7.45 (m, 1H).

EXAMPLE 89

[0800](3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0801] The title compound was synthesised as in Example 88. The yield ofthe final step was 3.4 mg, 5.8%.

[0802] MS [M-CF₃COO]⁺: 454

[0803]¹H-NMR (DMSO-d₆): δ 1.0-1.45 (m, 7H), 1.55-1.80 (m, 3H), 1.80-2.15(m, 5H), 2.32 (m, 1H), 2.95-3.05 (m, 2H), 3.20-3.52 (m, 6H), 3.52-3.68(m, 1H), 3.85-3.95 (m, 1H), 5.20 (m, 1H), 6.16 (s, 1H, OH), 7.0-7.04 (m,1H), 7.10-7.15 (m, 1H), 7.25-7.40 (m, 5H), 7.43-7.46 (m, 1H).

EXAMPLE 90

[0804]1-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2S)-2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0805] The title compound was synthesised as in Example 88. The yield ofthe final step was 8.4 mg, 12.7%.

[0806] MS [M-CF₃COO]⁺: 509

[0807]¹H-NMR (DMSO-d₆): δ 1.0-1.45 (m, 7H), 1.55-1.70 (m, 3H), 1.70-2.20(m, 7H), 2.31 (m, 1H), 3.20-3.27 (m, 1H), 3.25-3.50 (m, 5H), 3.45-3.60(m, 1H), 3.85-3.95 (m, 1H), 4.054.15 (m, 2H), 5.18 (m, 1H), 6.16 (s, 1H,OH), 7.0-7.03 (m, 1H), 7.13-7.15 (m, 1H), 7.28-7.31 (m, 1H), 7.43-7.46(m, 3H), 7.50-7.55 (m, 1H).

EXAMPLE 91

[0808](3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0809] The title compound was synthesised according to methods c, and bfrom Intermediate I-6b (The Intermediate I-6b used herein containsaprox. 25% of I-6a, see previous description in method c). The yield ofthe final step was 3.0 mg, 4.8%.

[0810] MS [M-CF₃COO]⁺: 484

[0811]¹H-NMR (DMSO-d₆): δ 1.0-1.50 (m, 7H), 1.55-2.22 (m, 10H),2.25-2.35 (m, 1H), 3.20-3.45 (m, 5H), 3.45-3.60 (m, 1H), 3.85-3.95 (m,1H), 4.04.10 (m, 2H), 5.17 (m, 1H), 6.14 (and 6.16) (s, 1H, OH, mixtureof diastereomers aprox. 75:25), 6.93-7.03 (m, 4H), 7.13-7.17 (m, 1H),7.28-7.35 (m, 2H), 7.42-7.45 (m, 1H).

EXAMPLE 92

[0812](3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0813] The title compound was synthesised as in Example 91. The yield ofthe final step was 2.6 mg, 4.4%.

[0814] MS [M-CF₃COO]⁺: 454

[0815]¹H-NMR (DMSO-d₆): δ 1.50-1.70 (m, 7H), 1.55-2.20 (m, 8H), 2.28 (m,1H), 2.95-3.10 (m, 2H), 3.20-3.52 (m, 6H), 3.52-3.65 (m, 1H), 3.85-3.97(m, 1H), 5.15-5.25 (m, 1H), 6.14 (and 6.16), (s, 1H, OH, mixture ofdiastereomers aprox. 75:25), 6.98-7.04 (m, 1H), 7.13-7.16 (m, 1H),7.25-7.40 (m, 5H), 7.43-7.46 (m, 1H).

EXAMPLE 93

[0816]1-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2R)-2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0817] The title compound was synthesised as in Example 91. The yield ofthe final step was 5.0 mg, 7.5%.

[0818] MS [M-CF₃COO]⁺: 509

[0819]¹H-NMR DMSO-d₆): δ 1.0-1.50 (m, 7H), 1.55-2.05 (m, 7H), 2.05-2.22(m, 3H), 2.22-2.35 (m, 1H), 3.20-3.50 (m, 6H), 3.45-3.60 (m, 1H),3.80-3.95 (m, 1H), 4.10-4.15 (m, 2H), 5.17 (m, 1H), 6.14 (and 6.16) (s,1H, OH, mixture of diastereomers aprox. 75:25), 7.0-7.03 (m, 1H),7.13-7.16 (m, 1H), 7.28-7.32 (m, 1H), 7.43-7.46 (m, 3H), 7.50-7.55 (m,1H).

EXAMPLE 94

[0820](3R)-3-(2-Hydroxy-4-phenyl-2-thien-2-ylbutanoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0821] The title compound was synthesised as a mixture of diastereomersaccording to methods d, and b from Intermediate I-21. The yield of thefinal step was 4.8 mg, 15.8

[0822] MS [M-CF₃COO]⁺: 506

[0823]¹H-NMR (DMSO-d): δ 1.75-2.05 (m, 3H), 2.05-2.20 (m, 2H), 2.20-2.35(m, 2H), 2.37-2.70 (m, 4H), 3.20-3.65 (m, 7H), 3.82-3.95 (m, 1H),4.0-4.1 (m, 2H), 5.12 (m, 1H), 6.58 (s, 1H, OH), 6.90-7.0 (m, 3H),7.0-7.08 (m, 1H), 7.14-7.24 (m, 4H), 7.24-7.36 (m, 4H), 7.46-7.52 (m,1H).

EXAMPLE 95

[0824](3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneBromide

[0825] The title compound was synthesised according to methods c, and afrom the Intermediate I-7. The yield of the final step was 250 mg,87.1%.

[0826] MS [M-Br]⁺: 470

[0827]¹H-NMR (DMSO-d₆): δ (Same description as in Example 53)

EXAMPLE 96

[0828](3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0829] The title compound was synthesised according to methods c, and bfrom the Intermediate I-7. The yield of the final step was 11.1 mg,40.2%.

[0830] MS [M-CF₃COO]⁺: 460

[0831]¹H-NMR (DMSO-d₆): δ (Same description as in Example 54)

EXAMPLE 97

[0832](3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0833] The title compound was synthesised as in Example 96. The yield ofthe final step was 11.3 mg, 41.4%.

[0834] MS [M-CF₃COO]: 454.

[0835]¹H-NMR (DMSO-d₈): δ (Same description as in Example 57).

EXAMPLE 98

[0836]4-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0837] The title compound was synthesised according to methods c, and bfrom the Intermediate I-8. The yield was 9.4 mg, 34.6%.

[0838] MS [M-CF₃COO]⁺: 468

[0839]¹H-NMR (DMSO-d₆): δ 0.90-1.65 (m, 9H), 1.70-1.80 (m, 1H),1.90-2.05 (m, 2H), 2.05-2.20 (m, 1H), 2.18-2.35 (m, 6H), 2.75-2.90 (m,2H), 3.10-3.25 (m, 2H), 3.45-3.70 (m, 6H), 5.60 (s, 1H, OH), 6.90-6.92(m, 1H), 6.95-7.02 (m, 1H), 7.20-7.45 (m, 4H), 7.50-7.60 (m, 2H).

EXAMPLE 99

[0840]4-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octaneTrifluoroacetate

[0841] The title compound was synthesised as in Example 98. The yield ofthe final step was 8.1 mg, 29.2%.

[0842] MS [M-CF₃COO]⁺: 478

[0843]¹H-NMR (DMSO-d₆): δ 0.90-1.65 (m, 9H), 1.70-1.80 (m, 1H),2.05-2.20 (m, 3H), 2.20-2.40 (m, 6H), 3.20-3.45 (m, 2H), 3.50-3.75 (m,6H), 3.95-4.10 (m, 2H), 5.60 (s, 1H, OH), 6.85-7.05 (m, 3H), 7.20-7.45(m, 5H), 7.50-7.65 (m, 2H).

[0844] ((*): Configuration not assigned)

[0845] The following examples illustrate pharmaceutical compositionsaccording to the present invention and procedures for their preparation.

EXAMPLE 100

[0846] Preparation of a Pharmaceutical Composition: Tablets

[0847] Formulation: Compound of the present invention  5.0 mg Lactose113.6 mg Microcrystalline cellulose  28.4 mg Light silicic anhydride 1.5 mg Magnesium stearate  1.5 mg

[0848] Using a mixer machine, 15 g of the compound of the presentinvention was mixed with 340.8 g of lactose and 85.2 g ofmicrocrystalline cellulose. The mixture was subjected to compressionmoulding using a roller compactor to give a flake-like compressedmaterial. The flake-like compressed material was pulverized using ahammer mill, and the pulverized material was screened through a 20 meshscreen. A 4.5 g portion of light silicic anhydride and 4.5 g ofmagnesium stearate were added to the screened material and mixed. Themixer product was subjected to a tablets making machine equipped with adie/punch system of 7.5 mm in diameter, thereby obtaining 3,000 tabletseach having 150 mg in weight.

EXAMPLE 101

[0849] Preparation of a Pharmaceutical Composition: Tablets Coated

[0850] Formulation: Compound of the present invention 5.0 mg Lactose95.2 mg  Corn starch 40.8 mg  Polyvinylpyrrolidone K25 7.5 mg Magnesiumstearate 1.5 mg Hydroxypropylcellulose 2.3 mg Polyethylene glycol 60000.4 mg Titanium dioxide 1.1 mg Purified talc 0.7 mg

[0851] Using a fluidized bed granulating machine, 15 g of the compoundof the present invention was mixed with 285.6 g of lactose and 122.4 gof corn starch. Separately, 22.5 g of polyvinylpyrrolidone was dissolvedin 127.5 g of water to prepare a binding solution. Using a fluidized bedgranulating machine, the binding solution was sprayed on the abovemixture to give granulates. A 4.5 g portion of magnesium stearate wasadded to the obtained granulates and mixed. The obtained mixture wassubjected to a tablet making machine equipped with a die/punch biconcavesystem of 6.5 mm in diameter, thereby obtaining 3,000 tablets, eachhaving 150 mg in weight.

[0852] Separately, a coating solution was prepared by suspending 6.9 gof hydroxypropylmethylcellulose 2910, 1.2 g of polyethylene glycol 6000,3.3 g of titanium dioxide and 2.1 g of purified talc in 72.6 g of water.Using a High Coated, the 3,000 tablets prepared above were coated withthe coating solution to give film-coated tablets, each having 154.5 mgin weight.

EXAMPLE 102

[0853] Preparation of a Pharmaceutical Composition: Liquid Inhalant

[0854] Formulation: Compound of the present invention 400 μgPhysiological saline  1 ml

[0855] A 40 mg portion of the compound of the present invention wasdissolved in 90 ml of physiological saline, and the solution wasadjusted to a total volume of 100 ml with the same saline solution,dispensed in 1 ml portions into 1 ml capacity ampoule and thensterilized at 1150 for 30 minutes to give liquid inhalant.

EXAMPLE 103

[0856] Preparation of a Pharmaceutical Composition: Powder Inhalant

[0857] Formulation: Compound of the present invention   200 μg Lactose4,000 μg

[0858] A 20 g portion of the compound of the present invention wasuniformly mixed with 400 g of lactose, and a 200 mg portion of themixture was packed in a powder inhaler for exclusive use to produce apowder inhalant.

EXAMPLE 104

[0859] Preparation of a Pharmaceutical Composition: Inhalation Aerosol.

[0860] Formulation: Compound of the present invention   200 μgDehydrated (Absolute) ethyl alcohol USP   8,400 μg1,1,1,2-Tetrafluoroethane (HFC-134A) 46,810 μg

[0861] The active ingredient concentrate is prepared by dissolving0.0480 g of the compound of the present invention in 2.0160 g of ethylalcohol. The concentrate is added to an appropriate filling apparatus.The active ingredient concentrate is dispensed into aerosol container,the headspace of the container is purged with Nitrogen or HFC-134A vapor(purging ingredients should not contain more than 1 ppm oxygen) and issealed with valve. 11.2344 g of HFC-134A propellant is then pressurefilled into the sealed container.

1. A compound of formula (I):

wherein B is a phenyl ring, a 5 to 10 membered heteroaromatic groupcontaining one or more heteroatoms, or a naphthalenyl,5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, or biphenyl group;R¹, R² and R³ each independently represent a hydrogen or halogen atom,or a hydroxy group, a phenyl group, —OR⁷, —SR⁷, —NR⁷R⁸, —NHCOR⁷,—CONR⁷R⁸, —CN, —NO₂, —COOR⁷ or —CF₃ group, or a straight or branched,substituted or unsubstituted lower alkyl group, wherein R⁷ and R³ eachindependently represent a hydrogen atom, a straight or branched loweralkyl group, or together form an alicyclic ring; or R¹ and R² togetherform an aromatic or alicyclic ring or a heterocyclic group. n is aninteger from 0 to 4; A represents a group selected from —CH₂—, —CH═CR⁹—,—CR⁹═CH—, —CR⁹R¹⁰—, —CO—, —O—, —S—, —S(O)—, —S(O)₂— and NR⁹, wherein R⁹and R¹⁰ each independently represent a hydrogen atom, a straight orbranched lower alkyl group, or together form an alicyclic ring; m is aninteger from 0 to 8, provided that when m=0, A is not —CH₂—; p is aninteger from 1 to 2 and the substitution in the azonia bicyclic ring maybe in the 2, 3 or 4 position including all possible configurations ofthe asymmetric carbons; R⁴ represents a group of structure:

wherein R¹¹ represents a hydrogen or halogen atom, a hydroxy group, analkoxy group, a nitro group, a cyano group, —CO₂R¹² or —NR¹²R¹³, whereinR¹² and R¹³ are identical or different and are selected from hydrogenand straight or branched lower alkyl groups, or a straight or branched,substituted or unsubstituted lower alkyl group; R⁵ represents an alkylgroup of 1 to 7 carbon atoms, an alkenyl group containing 2 to 7 carbonatoms, an alkynyl group containing 2 to 7 carbon atoms, a cycloalkylgroup of 3 to 7 carbon atoms, or a group of formula

wherein q=1 or 2 and R¹¹ is as defined above; R⁶ represents a hydrogenatom, a hydroxy group, a methyl group or a —CH₂OH group; and X⁻represents a pharmaceutically acceptable anion of a mono or polyvalentacid.
 2. A compound according to claim 1, wherein p is
 2. 3. A compoundaccording to claim 1 or claim 2, wherein R⁴ represents an unsubstitutedphenyl, 2-thienyl, 3-thienyl, 2-furyl or 3-furyl group.
 4. A compoundaccording to any one of the preceding claims, wherein R⁵ represents acyclopentyl, cyclohexyl, pentyl, allyl, vinyl, propynyl, benzyl orphenethyl group.
 5. A compound according to any one of the precedingclaims, wherein the group —O—CO—C(R⁴)(R⁵)(R⁶) represents a groupselected from 2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy;2,3-diphenylpropionyloxy; 2-hydroxymethyl-2,3-diphenylpropionyloxy;2-hydroxy-2,3-diphenylpropionyloxy;2-hydroxy-3-phenyl-2-thien-2-ylpropionyloxy;2-hydroxy-2-thien-2-ylpent-4-enoyloxy;2-hydroxy-2-thien-2-ylheptanoyloxy;2-hydroxy-2-thien-2-ylpent-3-ynoyloxy;2-hydroxy-2-thien-2-ylbut-3-enoyloxy;2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy;2-cyclohexyl-2-hydroxy-2-phenylacetoxy;2-cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy;2-cyclopentyl-2-hydroxy-2-phenylacetoxy,2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy and2-hydroxy-4-phenyl-2-thien-2-ylbutanoyloxy.
 6. A compound according toany one of the preceding claims, wherein B represents a phenyl,pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl,5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, imidazolyl orbenzothiazolyl group.
 7. A compound according to claim 6, wherein Brepresents a phenyl, pyrrolyl or thienyl group.
 8. A compound accordingto any one of the preceding claims wherein R¹, R² and R³ eachindependently represent a hydrogen or halogen atom or a hydroxy, methyl,tert-butyl, —CH₂OH, 3-hydroxypropyl, —OMe, —NMe₂, —NHCOMe, —CONH₂, —CN,—NO₂, —COOMe or —CF₃ group.
 9. A compound according to claim 8 whereinR¹, R² and R³ each independently represent a hydrogen or halogen atom ora hydroxy group.
 10. A compound according to any one of the precedingclaims, wherein n=0 or 1; m is an integer from 1 to 6; and A representsa —CH, —CH═CH—, —CO—, —NMe—, —O— or —S— group.
 11. A compound accordingto claim 10, wherein m is 1, 2 or 3 and A represents a —CH₂—, —CH═CH—,—O— or —S— group.
 12. A compound according to any one of the precedingclaims, wherein the azoniabicyclo group is substituted on the nitrogenatom with a group selected from 3-phenoxypropyl, 2-phenoxyethyl,3-phenylallyl, phenethyl, 3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl,3-(4-fluorophenoxy)propyl, 3-thien-2-ylpropyl, 4-oxo-4-thien-2-ylbutyl,2-benzyloxyethyl, 3-o-tolyloxypropyl, 3-(3-cyanophenoxy)propyl,3-(methylphenylamino)propyl, 3-phenylsulfanylpropyl,4-oxo-4-phenylbutyl, 3-(2-chlorophenoxy)propyl,3-(2,4-difluorophenoxy)propyl, 3-(4-methoxyphenoxy)propyl,3-(benzo[1,3]dioxol-5-yloxy)propyl.
 13. A compound according to any oneof the preceding claims, wherein X represents a chloride, bromide,trifluoroacetate or methanesulphonate anion.
 14. A compound according toany one of the preceding claims, wherein the azoniabicyclic group issubstituted in the 3-position.
 15. A compound according to claim 14,wherein the substituent at the 3-position of the azoniabicyclic grouphas R configuration.
 16. A compound according to claim 14, wherein thesubstituent at the 3-position of the azoniabicyclic group has Sconfiguration.
 17. A compound according to any one of the precedingclaims, wherein the carbon substituted by R⁴, R⁵ and R⁶ has Rconfiguration.
 18. A compound according to any one of claims 1 to 16wherein the carbon substituted by R⁴, R⁵ and R⁶ has S configuration. 19.A compound according to any one of the preceding claims, which is asingle isomer.
 20. A compound according to claim 1 which is:(3R)-3-(2,3-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2,3-Diphenylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxymethyl-2,3-diphenylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxymethyl-2,3-diphenylpropionyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxy-2,3-diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-(2-Hydroxy-2,3-diphenylpropionyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-(2-Hydroxy-3-phenyl-2-thien-2-ylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxy-3-phenyl-2-thien-2-ylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-(2-Hydroxy-2-thien-2-ylheptanoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxy-2-thien-2-ylheptanoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxy-2-thien-2-ylpent-3-ynoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxy-2-thien-2-ylpent-3-ynoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxy-2-thien-2-ylbut-3-enoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxy-2-thien-2-ylbut-3-enoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(4-oxo-4-thien-2-ylbutyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[4-(4-fluorophenyl)-4-oxobutyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate1-(2-Benzyloxyethyl)-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-o-tolyloxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate1-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(naphthalen-1-yloxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(methylphenylamino)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(2,4,6-trimethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate1-[3-(2-Chlorophenoxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy)-1-[3-(3-trifluoromethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate1-[3-(Biphenyl-4-yloxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(2,4-difluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate1-[3-(Benzo[1,3]dioxol-5-yloxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate1-[3-(2-Carbamoylphenoxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(3-dimethylaminophenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate1-[3-(4-Acetylaminophenoxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo(2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-methoxycarbonylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2:2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate1-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2S)-2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate1-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2R)-2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxy-4-phenyl-2-thien-2-ylbutanoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide(3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate4-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate4-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate
 21. A process for producing a compound of formula (I):

wherein R¹, R², R³, R⁴, R⁵, R⁶, p, m, n, A, B and X are as defined inany one of claims 1 to 18, which process comprises quaternising thenitrogen atom of the azoniabicyclic ring of a compound of formula (III):

wherein R⁴, R⁵, R⁶ and p are as defined above, with an alkylating agentof formula (II):

wherein R¹, R², R³, m, n, A and B are as defined above, and W representsa leaving group.
 22. A process according to claim 21, wherein Wrepresents a group X as defined in claims 1 or
 13. 23. A processaccording to claim 21 or claim 22, wherein the resulting reactionmixture is purified by solid phase extraction.
 24. A compound of formula(III)

wherein p, R4, R5 and R6 are as defined in claim 1, the substituent onthe azabicyclo group is at position 3 or 4 and when it is at position 3this substituted carbon has an enantiomerically pure R or Sconfiguration, provided that when R4 is a 3-thienyl group and R5 is acyclohexyl group R6 is not a hydroxy group.
 25. A compound according toclaim 24, wherein the substituent on the azabicyclo group is at position3 with R configuration.
 26. A compound according to claim 24, whereinthe substituent on the azabicyclo group is at position 3 with Sconfiguration.
 27. A compound according to any one of claims 24 to 26wherein the carbon substituted by R⁴, R⁵ and R⁶ has R configuration. 28.A compound according to any one of claims 24 to 26 wherein the carbonsubstituted by R⁴, R⁵ and R⁶ has S configuration.
 29. A compoundaccording to any one of claims 24 to 28, which is a single isomer.
 30. Acompound according to claim 24 which is:(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester;(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester;(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid(3R)—-azabicyclo[2.2.2]oct-3-yl ester;(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester;(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid1-azabicyclo[2.2.2]oct-4-yl ester
 31. A pharmaceutical compositioncomprising a compound according to any one of claims 1 to 20 inadmixture with a pharmaceutically acceptable carrier or diluent.
 32. Acompound according to any one of claims 1 to 20, or a pharmaceuticalcomposition according to claim 31, for therapeutic use in a method oftreatment of the human or animal body by therapy.
 33. Use of a compoundaccording to any one of claims 1 to 20, or a pharmaceutical compositionaccording to claim 31, in the manufacture of a medicament for thetreatment of a respiratory, urological or gastrointestinal disease ordisorder.
 34. A method of treating a respiratory, urological orgastrointestinal disease or disorder, which method comprisesadministering to a human or animal patient in need of treatment aneffective non-toxic amount of a compound according to any one of claims1 to 20 or a pharmaceutical composition according to claim
 31. 35. Acombination product comprising (i) a compound according to any one ofclaims 1 to 20; and (iii) another compound effective in the treament ofa respiratory, urological or gastrointestinal disease or disorder forsimultaneous, separate or sequential use.
 36. A combination productaccording to claim 35 comprising (i) a compound according to any one ofclaims 1 to 20; and (iv) a 02 agonist, steroid, antiallergic drug,phosphodiesterase IV inhibitor and/or leukotriene D4 (LTD4) antagonistfor simultaneous, separate or sequential use in the treatment of arespiratory disease.